Antitumor Extrolites Produced by Penicillium Species

Global Science Books; Rosario Nicoletti

Biodiversity is increasingly exploited worldwide for the finding of new pharmaceuticals. In relation to a competitive aptitude developed in many and diverse environments, microorganisms are able to produce secondary metabolites with cytotoxic and antiproliferative properties that are valuable in the perspective of antitumor drug discovery. Particularly, fungal species in the genus Penicillium represent a prolific source of biologically active extrolites that in some cases have already disclosed possible relevance for an application in cancer chemotherapy. Antiproliferative, pro-apoptotic, anti-angiogenic, anti-metastatic, DNA synthesis and cell cycle inhibitory properties of these compounds are reviewed in the present paper.

® International Journal of Biomedical and Pharmaceutical Sciences ©2008 Global Science Books Antitumor Extrolites Produced by Penicillium Species Rosario Nicoletti1* • Maria Letizia Ciavatta2 • Elisabetta Buommino3 • Maria Antonietta Tufano3 1 Council for Research and Experimentation in Agriculture - Research Unit of Scafati, Via Vitiello 108, 84018 Scafati, Italy 2 Institute of Biomolecular Chemistry, C.N.R., Via Campi Flegrei 36, Pozzuoli, Italy 3 Department of Experimental Medicine, the Second University of Naples, Via De Crecchio 7, 80100 Napoli, Italy Corresponding author: * rosario.nicoletti@entecra.it ABSTRACT Biodiversity is increasingly exploited worldwide for the finding of new pharmaceuticals. In relation to a competitive aptitude developed in many and diverse environments, microorganisms are able to produce secondary metabolites with cytotoxic and antiproliferative properties that are valuable in the perspective of antitumor drug discovery. Particularly, fungal species in the genus Penicillium represent a prolific source of biologically active extrolites that in some cases have already disclosed possible relevance for an application in cancer chemotherapy. Antiproliferative, pro-apoptotic, anti-angiogenic, anti-metastatic, DNA synthesis and cell cycle inhibitory properties of these compounds are reviewed in the present paper. _____________________________________________________________________________________________________________ Keywords: antiproliferative compounds, apoptosis, cancer chemotherapy, cell cycle inhibitors, Eupenicillium, fungal metabolites, Talaromyces Abbreviations: AML, acute myelogenous leukemia; bFGF, basic fibroblast growth factor; cdk, cyclin-dependent kinase; FTase, farnesyltransferase; GGTase, geranylgeranyltransferase I; GRP78, glucose-regulated protein 78; MMP, matrix metalloproteinase; PAI-1, plasminogen activator inhibitor-1; PI3K, phosphatidylinositol-3-kinase; pRB, retinoblastoma protein; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor CONTENTS INTRODUCTION.......................................................................................................................................................................................... 1 PENICILLIUM EXTROLITES: FROM MYCOTOXINS TO PHARMACEUTICALS................................................................................ 5 ANTIPROLIFERATIVE EXTROLITES ....................................................................................................................................................... 5 MICROTUBULE, CELL CYCLE AND DNA SYNTHESIS INHIBITORS............................................................................................... 10 ANGIOGENESIS INHIBITORS AND ANTI-METASTATIC COMPOUNDS........................................................................................... 15 EXTROLITES WITH OTHER MECHANISMS OF ANTITUMOR ACTIVITY ....................................................................................... 16 FUTURE PERSPECTIVES ......................................................................................................................................................................... 16 REFERENCES............................................................................................................................................................................................. 16 _____________________________________________________________________________________________________________ INTRODUCTION Recently, there is an increasing awareness of the importance for humanity to exploit natural resources to find new pharmaceuticals. After decades when the development of the pharmaceutical industry was essentially founded on synthetic chemistry, such instances have stimulated the search of novel natural products from diverse environments and organisms. In this context, secondary metabolites of microbial origin deserve special consideration, provided that it is generally possible to produce them on a large scale as a result of fermentative processes carried out in controlled conditions. The relevance of low molecular mass compounds remains undisputed in many fields of application in human medicine, but the breakthroughs that occurred in genetic engineering, cell and molecular biology have determined paramount progresses particularly in the therapy of tumor diseases. Moreover, the ongoing elucidation of the human genome is expected to provide access to many new potential targets that may be valuable for drug discovery. So far plenty of microbial products have been characterized at different levels for their antitumor properties; some Received: 4 January, 2008. Accepted: 23 March, 2008. of them have already entered pharmaceutical use, and novel ones are continuously discovered. This quite convulse accumulation of new findings is creating a fragmented knowledge that fosters an organization of the current experimental data on these compounds in order to accomplish a comprehensive overview. Several criteria of classification have been proposed and continuously revised as anticancer drug discovery progresses and novel mechanisms of action are pointed out. Most of them are not concurrent, as it is not easy to establish the primary organizing aspect that should be followed (Espinosa et al. 2003; Wu 2006). However, a classification of antitumor drugs based on their biological properties seems to be more fundamental as it allows an evaluation for classes of similar compounds. On the other hand, inferences on the mechanism of action can be made on account of their molecular structures that are helpful for a profitable definition of the appropriate biological assays (Cruciani et al. 2004). Within the multitude of micro-organisms so far exploited in this field, fungal species in the genus Penicillium stand out in both quantitative and qualitative terms, along the lines of the fruitful and ongoing experience of antibiotic Review International Journal of Biomedical and Pharmaceutical Sciences 2 (1), 1-23 ©2008 Global Science Books Table 1 Antitumor extrolites treated in this review and their producing Penicillium species. Extrolitea Producing species Acetophthalidin (38) Penicillium sp. Andrastins (46) Penicillium sp. P. albocoremium P. allii P. radicicola P. tulipae P. crustosum P. roqueforti P. paneum Anicequol (52) P. aurantiogriseum Asterric acid (48) and derivatives P. glabrum P. vulpinum P. aragonense P. estinogenum Aurantiamine (19) P. aurantiogriseum P. neoechinulatum P. freii Aurantiomides B-C P. aurantiogriseum Barceloneic acids P. concentricum P. albocoremium P. allii P. radicicola Berkeleyones (50) Penicillium sp. Berkelic acid Penicillium sp. Bis(methylthio)silvatin (7) P. brevicompactum P. bilaiae Bisvertinolones (11) P. chrysogenum P. crustosum Botryodiplodin (29) T. stipitatus P. brevicompactum P. carneum P. paneum P. coalescens Bredinin (26) E. brefeldianum Brefeldin A (22) P. decumbens P. cyaneum E. brefeldianum P. simplicissimum E. ehrlichii P. cremeogriseum P. onobense P. piscarium Brocaenols (1) P. brocae Chaetoglobosins (34) P. expansum P. marinum P. discolor Chrysophanol P. islandicum T. wortmannii Citreohybridones E. euglaucum Citromycins P. glabrum P. bilaiae P. striatisporum Communesins (4) P. marinum P. expansum P. rivulum Compactin (32) P. cyclopium P. hirsutum P. solitum P. lanosum P. aurantiogriseum P. janczewskii Cyclopiazonic acid (53) P. camemberti P. griseofulvum P. commune P. palitans P. dipodomycola P. clavigerum Dehydroaltenusin (25) T. flavus P. verruculosum P. simplicissimum Dehydroisopenicillide Penicillium sp. T. derxii P. simplicissimum 2 Reference Cui et al. 1996b Omura et al. 1996 Overy et al. 2005a Overy et al. 2005b idem idem Sonjak et al. 2005 Nielsen et al. 2005 O’Brien et al. 2006 Igarashi et al. 2002 Mahmoodian and Stickings 1964 Svendsen and Frisvad 1994 Pairet et al. 1995 database CBSb Frisvad and Filtenborg 1989 idem Lund and Frisvad 1994 Xin et al. 2007a Frisvad et al. 2004 Overy et al. 2005a Overy et al. 2005b idem Stierle et al. 2004 Stierle et al. 2006 Ayer et al. 1990 Capon et al. 2007 Frisvad et al. 2004 Liu et al. 2005a Fuska et al. 1988 Frisvad et al. 1989 Frisvad and Filtenborg 1989 Boysen et al. 1996 Cabedo et al. 2007 Mizuno et al. 1974 Singleton et al. 1958 Betina et al. 1962 Härri et al. 1963 Betina et al. 1966 Frisvad et al. 1990c Frisvad and Filtenborg 1990 idem idem Bugni et al. 2003 Frisvad and Filtenborg 1989 Numata et al. 1995 Frisvad et al. 1997 Howard and Raistrick 1949 Turner 1971 Kosemura et al. 1991 Evans and Staunton 1988 Capon et al. 2007 idem Numata et al. 1993 Larsen et al. 1998 Dalsgaard et al. 2005a Doss et al. 1986 Frisvad and Filtenborg 1989 idem Frisvad and Filtenborg 1990 Wagschal et al. 1996 Chu et al. 1999 Still et al. 1978 Leistner and Eckardt 1979 Frisvad 1985 idem Frisvad et al. 1987 Svendsen and Frisvad 1994 Fuska et al. 1991 Nakanishi et al. 1995 Komai et al. 2006b Sassa et al. 1974 Suzuki et al. 1991 Komai et al. 2006b Antitumor compounds from Penicillium. Nicoletti et al. Table 1 (Cont.) Extrolitea Deoxyverticillin Duclauxin (30) Emodin (41), Islandicin Epolactaene (44) Ergosterol derivatives Eupenifeldin (2) Farnesylquinones (10) Fellutamides (5) Fellutanines (6) Fumagillin (49) Fumitremorgins (39) GKK1032 (8) Gliotoxin (47) Griseofulvin (20) Hadacidin (27) HY558 (36) Isochromophilones Leptosphaerone C Luteusin A and analogues Methylenolactocin (13) 3-O-Methylfunicone (23) MT81 (42) Mycophenolic acid (28) Producing species Penicillium sp. P. duclauxii T. stipitatus P. herquei T. macrosporus P. islandicum P. brunneum P. janthinellum T. stipitatus Penicillium sp. P. oxalicum Penicillium sp. P. chrysogenum E. brefeldianum Penicillium sp. P. chrysogenum P. fellutanum P. fellutanum P. piscarium P. scabrosum P. janczewskii P. jamesonlandense P. soppii P. piscarium P. janthinellum P. raistrickii P. mononematosum P. brasilianum Penicillium sp. P. corylophilum P. glabrum P. griseofulvum P. janczewskii P. raistrickii P. sclerotigenum P. canescens P. concentricum P. dipodomycola P. aethiopicum P. coprophilum P. jensenii P. lanosum P. soppii P. persicinum P. waksmanii P. murcianum P. nodositanum P. yarmokense P. algidum P. jamesonlandense P. berlinense P. camemberti P. crustosum P. glabrum P. implicatum P. janthinellum P. purpurascens P. spinulosum P. turbatum P. minioluteum P. sclerotiorum Penicillium sp. T. luteus Penicillium sp. Penicillium sp. P. pinophilum P. janczewskii P. bialowiezense P. brevicompactum P. roqueforti P. carneum P. raciborskii P. rugulosum Reference Son et al. 1999 Shibata et al. 1965 Kuhr et al. 1973 Frisvad and Filtenborg 1990 Frisvad et al. 1990a Howard and Raistrick 1949 Shibata and Udagawa 1963 Marinho et al. 2005 Frisvad et al. 1990a Kakeya et al. 1995 Yang Kuo et al. 2005 Sun et al. 2006 Xin et al. 2007b Mayerl et al. 1993 Li et al. 2003 Maskey et al. 2005 Shigemori et al. 1991 Kozlovsky et al. 2000b Kozlovsky et al. 2000a Frisvad et al. 1990b Kwon et al. 2000 Frisvad et al. 2006 idem Gallagher and Latch 1977 Lanigan et al. 1979 Mantle and Wertheim 1982 Svendsen and Frisvad 1994 Tuthill et al. 2001 Hasegawa et al. 2001 Mull et al. 1945 Brian 1946 Oxford et al. 1939 Brian et al. 1949 Brian et al. 1955 Clarke and McKenzie 1967 El-Banna et al. 1987 idem Frisvad et al. 1987 Frisvad and Filtenborg 1989 idem Frisvad and Filtenborg 1990 idem Christensen et al. 1999 Wang et al. 2004 Petit et al. 2004 Larsen et al. 2005 idem idem Dalsgaard et al. 2005b Frisvad et al. 2006 Rebacz et al. 2007 Dulaney and Gray 1962 idem idem idem idem idem idem idem Lee et al. 2002a Omura et al. 1993 Lin et al. 2008b Fujimoto et al. 1990 Toki et al. 1999 Park et al. 1987 De Stefano et al. 1999 Gupta et al. 1997 Clutterbuck and Raistrick 1933 Clutterbuck and Raistrick 1933 Lafont et al. 1979 Frisvad and Filtenborg 1989 Frisvad and Filtenborg 1990 Vinokurova et al. 2005 3 International Journal of Biomedical and Pharmaceutical Sciences 2 (1), 1-23 ©2008 Global Science Books Table 1 (Cont.) Extrolitea Neoxaline Nidulalins (45) Oxaline (18) Oxazine derivative (15) Penicillenols Penicillenone C Penicillones (12) Penochalasins Penostatins Psychrophilin D Pyrenocines (3) Quinolactacins (55) Quinolinone derivatives (14) Rubratoxin B (37) Sch 642305 (16) Sclerotiorines (35) Secalonic acid D (21) Sequoiatones Shearinines (40) Sorbicillactone A (9) Taxol (17) Topopyrones (43) Trachyspic acid (51) Trichodimerols Vermistatin (24) Vermixocins (31) Verrucosidins (54) Verruculogen Producing species P. tulipae P. atramentosum P. coprobium P. coprophilum Penicillium sp. P. oxalicum P. atramentosum P. coprophilum P. glandicola P. melanoconidium P. vulpinum P. allii P. concentricum P. brevicompactum P. sizovae Penicillium sp. Penicillium sp. P. crustosum P. marinum P. marinum P. algidum E. euglaucum P. waksmanii P. paxilli Penicillium sp. P. citrinum P. bialowiezense P. sizovae P. cf. simplicissimum P. janczewskii Penicillium sp. P. rubrum P. purpurogenum P. verrucosum P. canescens P. sclerotiorum E. euglaucum T. luteus P. glabrum P. oxalicum P. dendriticum P. funiculosum P. minioluteum P. chrysogenum P. confertum P. funiculosum Penicillium sp. E. shearii P. janthinellum Penicillium sp. E. catenatum P. chrysogenum P. raistrickii Penicillium sp. T. trachyspermus P. chrysogenum P. crustosum T. flavus P. verruculosum E. euglaucum P. simplicissimum T. thailandiasis T. flavus Penicillium sp. P. aurantiogriseum P. polonicum P. melanoconidium P. verruculosum P. brasilianum P. piscarium P. janthinellum P. paxilli Reference Overy and Frisvad 2003 Frisvad et al. 2004 idem idem Sato et al. 1997 Nagel et al. 1974 Frisvad and Filtenborg 1989 idem idem idem idem Frisvad et al. 2004 idem Moya et al. 1998 Ciavatta et al. 2006 Lin et al. 2008a Lin et al. 2008b Liu et al. 2005c Numata et al. 1995 Takahashi et al. 1996 Dalsgaard et al. 2005b Niwa et al. 1980 Amagata et al. 1998 Rukachaisirikul et al. 2007 Kakinuma et al. 2000 Kim et al. 2001 Frisvad et al. 2004 database CBSb Hayashi et al. 1997 He et al. 2005 Uchida et al. 2006 Townsend et al. 1966 Natori et al. 1970 Chu et al. 2003 Nicoletti et al. 2007 Curtin and Reilly 1940 Udagawa, 1963 Fujimoto et al. 1990 Chidananda et al. 2006 Steyn 1970 Samson et al. 1989 Van Reenen-Hoekstra et al. 1990 idem Frisvad et al. 2004 idem Katayama et al. 1989 Lin et al. 2008b Belofsky et al. 1995 Smetanina et al. 2007 Xu et al. 2007 database CBSb Bringmann et al. 2003 Stierle et al. 1995 Kanai et al. 2000 Shiozawa et al. 1995 Warr et al. 1996 Liu et al. 2005b Fuska et al. 1979 Murtaza et al. 1997 Rusman 2006 Komai et al. 2006a Dethoup et al. 2007 Proksa et al. 1992 Burka et al. 1983 El-Banna et al. 1987 Frisvad and Filtenborg 1989 Lund and Frisvad 1994 Cole et al. 1972 Yoshizawa et al. 1976 Gallagher and Latch 1977 Lanigan et al. 1979 Cockrum et al. 1979 4 Antitumor compounds from Penicillium. Nicoletti et al. Table 1 (Cont.) Extrolitea Verruculogen Wortmannin (33) a b Producing species P. estinogenum P. raistrickii E. crustaceum P. mononematosum T. wortmanni T. flavus P. funiculosum P. duclauxii Reference Day et al. 1980 Mantle and Wertheim 1982 Horie et al. 1985 Svendsen and Frisvad 1994 Brian et al. 1957 MacMillan et al. 1972 Haefliger and Hauser 1973 Dodge and Sato 1995 Number in parentheses refers to the molecular structure represented in Table 1 Database of the Centraalbureau voor Schimmelcultures, Utrecht, the Netherlands: http://www.cbs.knaw.nl/databases/index.htm careful consideration for their possible implications in cancer therapy. Despite the history of antibiotics dating back at least to the discovery of an antibacterial compound by Gosio (1896), later characterized as mycophenolic acid, the Penicillia are tightly linked by the name itself to the discovery of penicillin that, after its quite accidental finding by Alexander Fleming in 1928, turned out to produce dramatically beneficial effects. Afterwards, antibiotic properties have been repeatedly evidenced for many other Penicillium extrolites, but their quite diverse mechanisms of action have led to a diversification in the pharmaceutical employment. Particularly, the availability of human and mammalian cell lines has allowed carrying out direct assays of cytostatic activity, thereby stimulating their consideration as candidate antitumor products. The discovery of apoptosis, or programmed cell death, and of the genes controlling it by means of a number of biomolecular factors has further refined the possibility to accomplish an accurate evaluation of their biological properties for the development of new therapeutic agents of cancer. Considering the complexity of cancer diseases, and of the biomolecular events involved into their onset, development and progression, there are many targets that can be evaluated in the search of new chemotherapeutic agents, and actually many compounds possess multiple mechanisms of action, ranging from a simple cytostatic effect to more complex interactions with gene expression and enzyme functions. Such variation is also reflected by quite diverse and sometimes peculiar molecular structures (Fig. 1), that represent a substantial basis for further studies aiming at exploring not only the foundations of their biological properties, but also the possibility to design new synthetic analogues. discovery. This paper provides a review of aspects concerning production, molecular structure and biological activity of their extrolites that have evidenced some extent of antitumor properties (Table 1). Taxonomically, Penicillium is the anamorphic stage of ascomycetous fungi belonging to the genera Eupenicillium and Talaromyces (Eurotiales, Trichocomaceae); the anamorph is of more general occurrence than the corresponding teleomorph, or perfect stage, and usually represents the form that can be isolated and cultured on artificial substrates. However, as the denomination of the teleomorph prevails in nomenclature, the species for which it has been described are cited in this review with such a reference, while species of Eupenicillium and Talaromyces presenting an anamorph other than Penicillium are not considered. After having been reported for the production of a certain extrolite, a number of Penicillium species have been separated by, or considered synonyms of other taxa deserving priority. Actually, the nomenclatural problem and its implications on a correct report of extrolite production have been adequately introduced and debated by leading specialists of chemotaxonomy (Frisvad et al. 2004; Larsen et al. 2005). Species are treated herewith under their latest accepted denomination, which therefore does not necessarily correspond to the one used in the pertinent references. However, the taxonomic revision that is continuously ongoing after the application of new biomolecular techniques may have already determined further changes in the species status of some taxa that we could not have considered in this manuscript. PENICILLIUM EXTROLITES: FROM MYCOTOXINS TO PHARMACEUTICALS In a broad sense, the term extrolite refers to any microbial secondary metabolite that is outwards directed with ecological implications (Larsen et al. 2005), that is either released or accumulated in the cell wall. As they are deputed to signalling to other organisms in the biocenosis, most of them are involved in competitive relationships, and present antifeedant and/or antibiotic activities. In fact, several Penicillium extrolites have been first described as mycotoxins and mostly considered for their toxicological properties that make their presence in foodstuffs and forage undesired. Generally, mycotoxins and antibiotics present cytotoxic effects that may have direct or indirect implications concerning cell division, thereby exhibiting the fundamental properties of typical antitumor products. However, some compounds cannot be included in this category, provided that their biological activity is not compatible with a pharmaceutical application under many aspects. In fact, the majority of data demonstrating their cytotoxic effect has been gathered in toxicological studies carried out on human or mammalian cells that have often pointed out notable genotoxic, teratogenic and/or carcinogenic properties (Ueno et al. 1995; Keblys et al. 2004); this is the case of compounds, such as citrinin, ochratoxin A, patulin, penicillic acid, alternariol and PR-toxin, that are not considered in this review. Nevertheless, other extrolites usually regarded as mycotoxins, such as cyclopiazonic acid, gliotoxin, secalonic acid D, the chatoglobosins and anthraquinone compounds, have disclosed interesting properties that may deserve a more ANTIPROLIFERATIVE EXTROLITES Any secondary metabolite showing cytostatic or antiproliferative properties on mammalian cells should be regarded as a potential antitumor compound. Based on this assumption, we first consider a number of Penicillium extrolites that have been preliminarily evaluated for their growth inhibitory aptitude on various tumor cells lines, and are possibly waiting to be further investigated for their biomolecular mechanisms of action. Brocaenols A-C (e.g. brocaenol A, 1), polyketides with some structural similarity to secalonic acids produced by a strain of P. brocae isolated from a Fijan sponge (Zyzzya sp.), were found to be cytotoxic against the human colon carcinoma cell line HCT116 (Bugni et al. 2003). Cytotoxic properties against the same cell line and the related multidrug resistant HCT/VM46, as well as in the P388 murine leukemia model, have been shown by the pentacyclic bistropolone eupenifeldin (2), isolated from E. brefeldianum (anamorph P. dodgei) (Mayerl et al. 1993). Inhibitory capacities against P388 have also been shown by the cyclic nitropeptide psychrophilin D (Dalsgaard et al. 2005b), the asterric acid analogue barceloneic acid B (Overy et al. 2005a), the polyketide penicillenone (Lin et al. 2008b), and the pyrenocines (e.g. citreopyrone, 3), so far detected in the three taxonomically unrelated species E. euglaucum (anamorph P. 5 International Journal of Biomedical and Pharmaceutical Sciences 2 (1), 1-23 ©2008 Global Science Books O OCH3 HO OH OCH3 O O O OH O H O O OH O 1 O O H HO 3 O O OH 2 NH2 N H O H N H OH O O O H N H N H O HN N H H O 5 H N 4 O NH2 O O H N OH N H3CS O N H3CN N H OH O 7 NCH3 O 6 SCH3 OH O NH OH OCH3 O HOOC O H O O O HO H OH N H H O OH O O 13 OH 9 H 8 HO 14 O OH O O N H H OH HO O O O O 12 O N H O HO O O HO 15 11 OH O HO H O O H O 10 O 6 16 Antitumor compounds from Penicillium. Nicoletti et al. O AcO OCH3 OH O NHCOPh O N Ph O OH OH H AcO OCOPh N O N HN OCH3 17 O OCH3 H O OCH3 O N H 18 HN NH NH O N H O H3CO OH H O Cl 19 O OH H O 20 OH O HO H H OH O 21 O 22 COOCH3 COOCH3 O O OCH3 COOCH3 OH OCH3 H3CO O 23 OH OH O O H N OH O H2NOC O O OCH3 H OCH3 O HOH2C N O HC O OH N CH2COOH 27 O HO H3CO O O 25 24 OH HO OH O COMe O OH O 26 COOH HO O O O HO OCH3 H OCH3 O 29 AcO O 28 H O H O OH O O O O HO OH O O 30 OCH3 32 31 7 International Journal of Biomedical and Pharmaceutical Sciences 2 (1), 1-23 ©2008 Global Science Books Cl O H3COCO O H3CO O H H O O AcO O O O 35 HN O N H O 33 O OH 34 OH H3C(H2C)5 OH O CH3(CH2)19NHNHOH 36 HO O O O H OH OH O O OH O O OH O 38 O OH N OH N O H3CO N H 37 O O 39 H OH OH O OH H O N H O OH O 40 O O 41 OH O O O OH O O OH O COOCH3 O N H 44 O O HO OH HO O 42 43 O O OH O H CHO O H N OH H H3COOC OH S N O O H3COOC OH H3COCO S CH2OH H 45 46 8 47 Antitumor compounds from Penicillium. Nicoletti et al. O OCH3 HO O COOH O O COOH O OCH3 HOOC COOCH3 O OH COOH COO 48 COOH 51 49 O N O OH O H OH H O HO O O NH O H H3CO 50 O 53 O H H HO OH 52 O O OCH3 O O O O NH H N O O 54 55 Fig. 1 Chemical structures of antitumor extrolites numbered according to their citation in the main text. HeLa (cervix-uteri carcinoma) and K562 (myeloid leukemia) (Kozlovsky et al. 2000b). Another diketopiperazine, cis-bis(methylthio)silvatin (7), already known from P. brevicompactum (Ayer et al. 1990), has been recently extracted by a marine isolate of P. bilaiae together with the polyketides citromycin and dihydrocitromycin that were also found in an isolate of P. striatisporum; all the three extrolites displayed weak cytotoxicity against murine NS-1 cells (Capon et al. 2007). Inhibitory properties against HeLa cells have been also exhibited by compounds GKK1032 A1, A2 (8) and B, extracted by an unidentified Penicillium strain (Hasegawa et al. 2001). Antiproliferative activity by sorbicillactone A (9), characterized from a strain of P. chrysogenum recovered from the marine sponge Ircinia fasciculata, has been reported against mouse lymphoma cells (L5178Y) (Bringmann et al. 2003), together with the analogue compounds sorbivinetone and sorbivinetol, inducing cytotoxic effects on HeLa and PC12 cells at much higher concentrations (Bringmann et al. 2005). An unidentified marine strain has been found to produce other structurally related extrolites, deacetoxyyanuthone A (10) and farnesylhydroquinone, whose cytotoxic properties have been pointed out on a panel of human tumor cell lines, including A549 (non-small cell lung carcinoma), SK-OV-3 (ovary adenocarcinoma), SK-MEL-2 (melanoma), HCT15 (colon cancer) and XF498 (central nervous system cancer) (Li et al. 2003). Deacetoxyyanuthone A has been also isolated by P. chrysogenum (syn. P. notatum: Maskey et al. 2005), a well-known producer of other bisorbicillinoid compounds, such as the bisvertinolones (Frisvad et al. 2004). More recently four novel compounds of this series have been reported from an isolate of marine origin ascribed to P. terrestre (Liu et al. 2005a, 2005b), a species considered as a synonym of P. crustosum in the current taxonomy (Frisvad and Samson 2004): dihydroand tetrahydrobisvertinolone (11) were found to be the most active products against P388 and A549 (Liu et al. 2005a). citreonigrum, syn. P. citreoviride) (Niwa et al. 1980), P. waksmanii (Amagata et al. 1998) and P. paxilli (Rukachaisirikul et al. 2007). Moderate cytotoxicity against P388 has been evidenced by the new quinazoline alkaloids aurantiomides B and C; moreover the compounds respectively induced cytotoxic effects against HL-60 (human promielocytic leukemia) and BEL-7402 (human hepatoma) (Xin et al. 2007a). Cytotoxicity against HL-60 has been shown by the pyrrolidinedione derivatives penicillenols A1 and B1 that have been characterized from an unidentified endophytic strain (Lin et al. 2008a). Communesins (A-H) (e.g. communesin A, 4), also known as nomofungins, are alkaloids with a peculiar and quite complex carbon skeleton extracted from marine strains (Numata et al. 1993; Jadulco et al. 2004), later identified as P. marinum (Frisvad et al. 2004); these extrolites have also been reported from the common species P. expansum (Larsen et al. 1998), and the recently characterized psychrotolerant species P. rivulum (Dalsgaard et al. 2005a). Communesins showed antiproliferative effects against both P388 (Numata et al. 1993) and the human acute lymphoblastic leukemia cell lines SUP-B15 and MOLT-3 (Jadulco et al. 2004). The lipo-tripeptides fellutamides A (5) and B, isolated from the mycelium of an isolate of P. fellutanum (synonym P. dierckxii) from the marine fish Apogon endekataenia, were found to be cytotoxic against murine leukemic P388 and L1210 (Shigemori et al. 1991) and other cell lines, such as KB (human epithelial carcinoma), PC12 (rat pheochromocytoma) and L-M (mouse fibroblasts), on which their possible mechanism of action is thought to be protease or proteasome inhibition (Schneekloth et al. 2006). Together with P. piscarium (Kozlovsky et al. 2000a), which is considered here separately by its possible synonym P. simplicissimum, P. fellutanum also produces the diketopiperazine alkaloids fellutanines A-D; fellutanine D (6) has been reported for its cytotoxic properties against murine fibroblasts L929, and the human cell lines 9 International Journal of Biomedical and Pharmaceutical Sciences 2 (1), 1-23 ©2008 Global Science Books Liu et al. (2005b) also reported cytotoxic activity on the same cell lines by dihydro- and tetrahydrotrichodimerol, which are derivatives of trichodimerol, an extrolite able to inhibit production of the tumor necrosis factor (TNF-) in murine macrophages and human peripheral blood monocytes, which had been formerly reported as BMS-182123 by P. chrysogenum (Warr et al. 1996). The above-reported marine isolate of P. crustosum was also found to produce two polyketides with a tricyclo-undecane skeleton named penicillone A (12) and B, that again proved to be cytotoxic against P388 and A549 (Liu et al. 2005c). It must be remarked here that the compound more recently found in an endophytic isolate of P. paxilli, also named penicillone (Rukachaisirikul et al. 2007), has a different molecular structure and should not be confused. Cytotoxicity against A549 cells was exhibited by the polyketide compound leptosphaerone C (Lin et al. 2008b). In the same paper, inactivity towards A549 and P388 is reported for sequoiatones A and B, which previously displayed moderate inhibitory properties against several breast cancer cell lines (Stierle et al. 1999). Ehrlich ascites cells inoculated intraperitoneally in mice were used to evidence the antitumor properties of methylenolactocin, -methylene--lactone (13) characterized from an unidentified Penicillium species (Park et al. 1987). Weak to moderate cytotoxicity against several human tumor cells, such as MDA-MB231 (breast adenocarcinoma), DU145 (prostate carcinoma), HT-29 (colon carcinoma), CAKI1 (kidney carcinoma), SK-OV-3, SK-MEL 2, A549 and K562, was exhibited by the quinolinone compounds yaequinolinone A2 (3R*,4R*-dihydroxy-3,4-dihydro-4-(4'-methoxyphenyl)-2(1H)-quinolinone, 14) and peniprequinolone, produced by some species belonging to the subgenus Furcatum (He et al. 2005; Uchida et al. 2006). Finally, the brevioxime analogue 2-(hept-5-enyl)-3-methyl-4-oxo-6,7,8,8atetrahydro-4H-pyrrolo[2,1-b]-1,3-oxazine (15, onwards mentioned as oxazine derivative), first detected in P. brevicompactum (Moya et al. 1998) and recently extracted from two isolates of P. sizovae (Ciavatta et al. 2006), and compound Sch 642305 (16), characterized from P. verrucosum (Chu et al. 2003), and later found as a fungitoxic extrolite of P. canescens (Nicoletti et al. 2007), have demonstrated antiproliferative and pro-apoptotic properties on MCF-7 (breast cancer) and A549 cells (Nicoletti et al. 2008), that are currently the subject of further investigations. neovascularization induced by the basic fibroblast growth factor (bFGF) and the vascular endothelial growth factor (VEGF) (Klauber et al. 1997). Several other natural products act more substantially by inhibiting the formation of the mitotic spindle. They have been grouped into two subclasses according to whether or not they bind tubulin to the same site as colchicine (Desbène and Giorgi-Renault 2002). Compounds belonging to the first subclass, such as the podophyllotoxins, steganacin, combretastatin and the colchicine itself, present a molecular structure sharing a trimethoxyphenyl moiety which is highly reactive with sulphydryl groups of aminoacids and represents an important binding site. This kind of active site can be also observed in the case of a Penicillium extrolite, 3-O-methylfunicone, that is treated in detail below. Oxaline (18) and neoxaline are alkaloids produced by several Penicillium species by transformation of roquefortine, a quite common diketopiperazine extrolite (Steyn and Vleggaar 1983). These compounds are able to inhibit cell proliferation and to induce cell cycle arrest at the M phase in T lymphoma Jurkat cells. Moreover, oxaline induces the disruption of microtubule assembly in mouse 3T3 fibroblasts, as a consequence of its ability to inhibit the polymerization of microtubule proteins; in vitro, purified tubulin is bound at the colchicine binding site (Koizumi et al. 2004). Aurantiamine (19), produced by P. aurantiogriseum and some closely related species, is another diketopiperazine reported to exert its biological activity on microtubule assembly (Hayashi et al. 2000). Mechanisms of tubulin binding have not been clearly elucidated in the case of griseofulvin (20), an extrolite produced by many Penicillium species and commonly used in the past as an antimicotic pharmaceutical against dermatophytes. Its anti-mitotic properties have been considered for their implications in cancer therapy since long time (Grisham et al. 1973). Yet, the compound is responsible for a mild suppression of microtubule dynamics that impairs the organization and function of the mitotic spindle, an effect that in HeLa cells halts cell cycle progression at the G2/M phase with ensuing apoptosis induction (Panda et al. 2005). Moreover, it has been found to induce multipolar spindles by inhibition of centrosome coalescence, mitotic arrest, and subsequent cell death in the human tumor cell lines SCC114 (oral cancer), HeLa, MCF-7, U2OS (osteosarcoma). This effect is selective, as it has not been observed in diploid fibroblasts and keratinocytes with normal centrosome content. The inhibition of centrosome clustering by griseofulvin is not restricted to mitotic cells but occurs during interphase as well. Most neoplastic cells contain multiple centrosomes, associated with the formation of multipolar mitotic spindles and chromosome segregation defects. Since it has been observed that tumor cells regain mitotic stability by the coalescence of multiple centrosomes into two functional spindle poles, a therapeutic strategy may be based on the inhibition of centrosomal clustering, which would trigger apoptosis by forcing multipolar mitoses in cells with supernumerary centrosomes (Rebacz et al. 2007). The reported mechanism of action of griseofulvin and its low toxicity introduce interesting perspectives for its use in combination with other antitumor agents. Ho et al. (2002) observed a synergism with nocodazole in determining inhibitory effects on tumor growth in mice bearing COLO 205 xenografts. They also found some clues of a direct effect on the cell cycle based on an increase in cyclin B1/cdc2 kinase activity and in a down-regulation of myt-1 protein expression; in addition, caspase 3 activation, Bcl-2 hyperphosphorylation and inhibition of the normal function of Bcl-2 associated with Bax were demonstrated to be the mechanisms responsible for apoptosis induction. The octaketide mycotoxin secalonic acid D (21) is known to be produced by P. oxalicum and several taxonomically unrelated species. Antitumor properties were first evidenced in its 5-di-(2'-tetrahydropyranyl) derivative assayed on murine cell lines and mice implanted tumors (Iwaguchi et al. 1980; Shimizu et al. 1983). Afterwards, the MICROTUBULE, CELL CYCLE AND DNA SYNTHESIS INHIBITORS Cytostatic and antiproliferative properties are based on inhibition of mitosis that occurs as a consequence of perturbations in the cell cycle, or in the DNA synthesis, or in the microtubule organization, effects that are often interrelated. Particularly, many successful antitumor drugs interfere with microtubule dynamics by mechanisms based either on the inhibition of tubulin polymerization, or on the stabilization of microtubule bundles (Desbène and Giorgi-Renault 2002; Jordan and Wilson 2004). The best known compound representing the latter class is taxol (17), also known as paclitaxel, which determines cell cycle arrest at the G2/M phase and subsequent apoptosis in consequence of interference in the microtubule dynamics. This highly functionalized diterpene was first extracted by the yew tree (Taxus brevifolia) (Wani et al. 1971), but afterwards found to be produced by several endophytic fungi, including a Penicillium species (P. raistrickii) (Stierle et al. 1995). The compound is undoubtedly the most important antitumor agent produced by Penicillium, as it has entered routine pharmaceutical use since almost a decade after having been approved for breast and ovarian cancer treatment (Demain 1999). A thorough review on the antitumor properties of paclitaxel and its analogue docetaxel considering its microtubule-targeted and other biomolecular effects has been recently published (Zhao et al. 2005). However, it must be also remarked that the drug may exert useful antiangiogenic side effects, as it has been reported to inhibit 10 Antitumor compounds from Penicillium. Nicoletti et al. 3-O-Methylfunicone (23), characterized from P. pinophilum (De Stefano et al. 1999), is one of a series of structurally related compounds mostly characterized by species belonging to the subgenus Biverticillium and their Talaromyces teleomorphs (Nicoletti and Carella 2004), whose skeleton consists in a -pyrone ring linked through a ketide function to an -resorcylic acid nucleus presenting a methylated carboxylic group. This extrolite is fungitoxic and responsible of the antagonistic properties toward plant pathogenic fungi (De Stefano et al. 1999; Nicoletti et al. 2004); moreover, it has displayed cytostatic and pro-apoptotic properties on several human tumor cell lines, such as HEp-2 (larynx carcinoma) (Stammati et al. 2002), A549 and MCF7 (Nicoletti et al. 2008). Investigations carried out on HeLa cells have demonstrated its ability to cause growth arrest, modification in the organization of tubulin fibers and apoptosis, which is triggered following a p53 independent pathway (Buommino et al. 2004). An increase in p21 mRNA expression and a reduced expression of cyclin D1 and cdk 4 mRNA resulted at the same time. Besides the pro-apoptotic properties, the compound has been found to inhibit the gene expression of typical markers of tumor progression, such as survivin and human telomerase reverse transcriptase, and to strongly affect cell proliferation and motility of breast cancer MCF-7 cells by down-regulating v5 integrin and inhibiting matrix metalloproteinase (MMP-9) secretion. This effect is selective, as it was not observed on a non-tumoral breast cell line (MCF-10) (Buommino et al. 2007). Inhibition of cell motility is also associated to modifications in cell shape and in the distribution of tubulin fibers of MCF-7 cells. As introduced above, this latter property may depend on the trimethoxylated aryl moiety; assays on its effect on tubulin polymerization are currently in progress in our laboratories to check this hypothesis. Another funicone-like extrolite, vermistatin (24), has been characterized by T. flavus (anamorph P. dangeardii, synonym P. vermiculatum) (Fuska et al. 1979, 1986), and later found to be produced by P. verruculosum (Murtaza et al. 1997) and P. simplicissimum (Komai et al. 2006a). Cytotoxicity of the compound was first observed on leukemic cells (Fuska et al. 1979), but further evidences of its antitumor properties have been gathered more recently. In fact a weak activity of vermistatin was detected against L5178Y cells; moreover the compound proved to be slightly inhibitory toward several kinases, such as aurora A and B, cdk 4/cyclin D1, the insulin-like growth factor I receptor, ErbB2, BRAF-VE, Akt1 and VEGF receptor-2 involved in the cell cycle progression and apoptosis induction, or implicated in the pathologic angiogenesis associated with tumor growth (Rusman 2006). Very recently some funicone and vermistatin analogues, described as penicidones and differing by a pyridone nucleus substituting the -pyrone ring, have been reported from an unidentified endophytic strain, and exhibited moderate cytotoxicity against several cell lines, such as KB, K562, HeLa and SW1116 (human colon cancer) (Ge et al. 2008). Dehydroaltenusin (25) has been found in the same species that produce vermistatin, that is T. flavus (Fuska et al. 1991), P. verruculosum (Nakanishi et al. 1995) and P. simplicissimum (Komai et al. 2006b): Rather than being occasional, these findings may be considered indicative of a common biosynthetic pathway shared by these extrolites. The compound showed cytostatic properties in preliminary tests carried out on P388 cells (Proksa et al. 1992), and was later found to inhibit the proliferation of human tumor cell lines, such as A549, BALL-1 (acute lymphoblastoid leukemia), NUGC3 (stomach carcinoma) and HeLa (Murakami-Nakai et al. 2004). Solid tumor development was suppressed as well in nude mice bearing HeLa cells, where histopathological examination revealed an increased tumor necrosis and a reduction of the mitotic index (Maeda et al. 2007). Biological activity of the compound relies on inhibition of DNA synthesis, which depends both on a direct inhibition of mammalian DNA polymerase and on an indirect effect following intercalation and conformational changes of the compound itself showed cytostatic activity against L1210 cells (Kurobane et al. 1987), and later found to affect proliferation of murine embryonic palatal mesenchymal cells (Hanumegowda et al. 2002). On these cells the compound inhibits G1/S-phase specific cyclin-dependent kinase 2 (cdk 2) activity, reduces the level of cyclin E and increases the level of the cdk inhibitor p21; the same effects are induced on the corresponding human cell type, together with a reduction in the level of cdk 4/6 and cyclins A, D1, D2, D3, E, while the level of the cdk inhibitor p57 is increased (Dhulipala et al. 2005). Brefeldin A (22), also known as ascotoxin, cyanein, decumbin, and synergisidin after its independent discovery in different fungal species (Singleton et al. 1958; Betina et al. 1962; Härri et al. 1963), is a macrocyclic lactone produced by a number of Eupenicillium and Penicillium species in the subgenus Furcatum. Its major biological activity was at first identified in the inhibition of intracellular protein transport from the endoplasmic reticulum to the Golgi apparatus, and the induction of a reversible disassembly of the latter (Fujiwara et al. 1988). Although this mechanism is important for tumor proliferation, it has been observed that the Golgi apparatus structure is unaffected in resistant cancer cell sublines (Erokhina et al. 1999). Actually, more consistent antitumor properties were evidenced on account of an antiproliferative activity detected in human melanoma athymic mouse xenografts and in PC3 prostate carcinoma cells (Sausville et al. 1996), while a pro-apoptotic effect resulted on HT-29 and a couple of human leukemic cell lines (HL60, K562), evidencing DNA fragmentation with the typical internucleosomal pattern. Cell death is independent of a cyclin B1/cdc2 kinase upregulation, as their activity decreased after brefeldin A treatment in HL-60 cells, and clearly occurs following a p53-independent pathway, as HL-60 and K562 cells are p53 null and HT-29 are p53 mutant cells (Shao et al. 1996). These effects, resulting in an arrest in the G1 to S phase transition of the cell cycle, have been confirmed on another prostatic cancer cell line (DU145) (Chapman et al. 1999). Since p53 mediated pathways is frequently abrogated in prostatic cancer cells, agents inducing p53 independent cell death may be promising chemotherapeutic candidates (Wallen et al. 2000). Properties as a direct cell cycle modulator in PC3 cells depend on the effect on a growth pathway mediated by the retinoblastoma protein (pRB); in fact, the compound induces dephosphorylation of pRB, and a down-regulation of cyclin-dependent kinases (cdk 2/4) and cyclin D1 expression (Mordente et al. 1998). pRB hypophosphorylation has been again observed on primary prostate cancer cells (Wallen et al. 2000). Treatment with brefeldin A triggers apoptosis after arresting cell cycle in early G0/G1 phase on other cell lines, such as HCT116 and glioblastoma (SA4, SA146 and U87MG), with no alteration of p53, Bcl-2, Bax and Mcl-1 expression (Pommepuy et al. 2003); differentiation of the latter cell line is induced as a result of a modulatory effect by brefeldin-A on GM3 ganglioside biosynthesis, that introduces a new therapeutic target for cancer diseases (Nojiri et al. 1999). In fact, as GM3 ganglioside is able to down-regulate tetraspanin CD9 that is associated with control of tumor cell motility, its enhanced synthesis induced by brefeldin A treatment may reduce the invasiveness of bladder cancer cells and, consequently, their metastatic properties (Satoh et al. 2001). Observations carried out on cytotoxicity and induction of apoptosis in HCT116 cells have shown that the structural determinants for biological activity of the compound include the moiety of the Michael acceptor, the conformational rigidity of the 13-membered ring, and the configuration of the hydroxyl group at C-4 (Zhu et al. 2000). Very recently the inhibitory properties against the functions of the endoplasmic reticulum-Golgi transport apparatus have been reappraised as the compound, based on ensuing mitochondrial breach and subsequent caspase cascade activation, was successful in inducing apoptosis on several follicular lymphoma cell lines that are resistant to conventional anticancer agents (Wlodkowic et al. 2007). 11 International Journal of Biomedical and Pharmaceutical Sciences 2 (1), 1-23 ©2008 Global Science Books DNA molecule (Mizushina et al. 2000a). DNA does not seem to be damaged, as there is no influence on p53, bax and bcl-2 expression levels, and fragmentation only occurs when HeLa cells are treated at higher concentrations. These effects halt the cell cycle at the S phase, which is confirmed by the increased levels of cyclins A and E, while a significant reduction occurs in levels of cyclin B, which is regulated at the G2/M phase (Murakami-Nakai et al. 2004). Bredinin (26), characterized from E. brefeldianum (Mizuno et al. 1974), is an imidazole nucleoside antibiotic with potent cytotoxicity. Its aglycone is able to induce very similar effects, as it is active after conversion to bredinin catalysed by the enzyme adenine-phosphoribosyltransferase (Sakaguchi et al. 1975a). The compound inhibits proliferation of several mammalian cell lines; on L5178Y cells it causes marked chromosomal aberrations, such as breakages, translocations, and fragmentation, and inhibits nucleic acid synthesis without being intercalated (Sakaguchi et al. 1975b). Bredinin-resistant mutants have been found in cultured mouse mammary carcinoma FM3A cells as a consequence of a defective adenosine-kinase, an enzyme that in sensitive cells phosphorylates bredinin to a toxic nucleotide, bredinin 5'-monophosphate (Koyama and Tsuji 1983). Cell growth inhibitory effects by this derivative were confirmed again on L5178Y (Kusumi et al. 1989). Later, bredinin 5'monophosphate also showed potent inhibitory effects on mammalian DNA polymerase and (Horie et al. 1998). Hadacidin (N-formyl hydroxyaminoacetic acid, 27), probably the structurally simplest antitumor extrolite in Penicillium, was characterized from isolates belonging to several species (Dulaney and Grey 1962), and soon found effective in the inhibition of growth of a human adenocarcinoma transplanted in embryonated eggs (Kaczka et al. 1962). The compound was also reported to be able to affect purine biosynthesis (Shigeura and Gordon 1962). Later this biological property was found to be dependent on a competitive inhibition of adenylosuccinate-synthetase, an enzyme involved in adenine nucleotide biosynthesis, resulting in an antiproliferative activity on canine kidney MDCK cells, whose cell cycle was arrested in the S phase (Ladino et al. 1989). Mycophenolic acid (28) is undoubtedly one of the first microbial metabolites to have been characterized (Gosio 1896), although an appropriate species determination of the producing strains occurred much later (Clutterbuck and Raistrick 1933). Probably it was also one of the first extrolites to have been studied for its possible use as an antitumor pharmaceutical, after substantial evidence to this regard resulted by laboratory assays carried out on several murine implanted tumors (Williams et al. 1968; Suzuki et al. 1969; Sweeney et al. 1972). Mycophenolic acid depletes guanine nucleotides and blocks DNA synthesis by inhibiting inosine monophosphate-dehydrogenase (Franklin and Cook 1969), an enzyme representing a valuable chemotherapeutic target, as it is particularly active in cancer cells (Franchetti and Grifantini 1999). In nanomolar concentrations the compound blocks proliferative responses of cultured human, mouse and rat T and B lymphocytes (Eugui et al. 1991). The more potent cytostatic effect observed on lymphocytes explains why mycophenolic acid is better considered as an immunosuppressive compound. In fact, its mofetil ester is a widespread pharmaceutical used in organ transplantation (Lipsky 1996). For the same reason, therapeutic application may be indicated in lymphocytic or monocytic leukemiae and lymphomas. DNA synthesis inhibition is a reported mechanism of action of botryodiplodin (or botryodiploidin) (29) and of the isocoumarin dimer duclauxin (30). Both extrolites are produced by P. stipitatum (synonym P. emmonsi, teleomorph T. stipitatus) (Fuska et al. 1988); moreover, the former has been reported by P. brevicompactum (Frisvad et al. 1989), P. coalescens (Cabedo et al. 2007) and P. paneum (Boysen et al. 1996), a species separated by the better known P. roqueforti from which the compound had been originally reported (Moreau et al. 1982), while the latter was first characterized by P. duclauxii (Shibata et al. 1965), and afterwards found to be also produced by T. stipitatus (Kuhr et al. 1973; Fuska et al. 1974), T. macrosporus (anamorph P. macrosporum) (Frisvad et al. 1990a) and P. herquei (Frisvad and Filtenborg 1990). Both extrolites showed antiproliferative activity against HeLa cells and murinederived cell lines (Ehrlich ascites, L-5178, sarcoma 37), and caused the inhibition of incorporation of 14C-labelled precursors of proteins and nucleic acids (Fuska et al. 1974). Inhibitory effects on DNA and RNA synthesis were again reported by Moulé et al. (1981), and referred to the induction of DNA-protein cross-links depending on the hemiacetal structure of the molecule (Douce et al. 1982; Moulé et al. 1982). Cross-links disappeared as soon as cells were transferred into fresh medium (Moulé et al. 1984). Duclauxin also exhibited inhibitory properties against L1210 cells, with a potent uncoupling effect accompanying a marked depression of state 3 respiration of mitochondria (Kawai et al. 1985). Vermixocins (e.g. vermixocin A, 31), detected as fermentation by-products of T. flavus, are able to inhibit the incorporation of labeled uridine into P388 cells, indicating that they may interfere with RNA synthesis (Proksa et al. 1992). Their structural analogue dehydroisopenicillide, isolated from unidentified Penicillium strains (Sassa et al. 1974; Kawamura et al. 2000) and from T. derxii (anamorph P. derxii) (Suzuki et al. 1991), has shown antiproliferative properties against several human cell lines, such as K562, MKN28 (gastric cancer), PC6 (lung cancer), MCF-7, HT1080 (fibrosarcoma) and HT29 (Kawamura et al. 2000). Compactin (32), also known as mevastatin, is a nonaketide characterized independently and almost contemporarily by P. brevicompactum (Brown et al. 1976) and P. citrinum (Endo et al. 1976). Both producing isolates were later found to have been mistakenly identified, and ascribed to P. solitum and P. hirsutum (Frisvad and Filtenborg 1989). Further reports are known from P. cyclopium (Doss et al. 1986), P. lanosum (Frisvad and Filtenborg 1990) and P. aurantiogriseum (Wagschal et al. 1996), and some biologically active structural analogues, such as dihydrocompactin (Lam et al. 1981), solistatin (Sørensen et al. 1999) and solistatinol (Larsen et al. 2007), are also produced by these species. Compactin is the founder of a family of compounds of both natural and synthetic origin known as the statins, which are widely employed for cardiovascular diseases. However, several large-scale trials of these drugs evidenced a beneficial side effect on patients suffering for cancer (Wong et al. 2002; Jakobisiak and Golab 2003), that introduced a new field for their pharmaceutical employment (Chan et al. 2003). Particularly, the fundamental mechanism of action has been identified in the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A-reductase, which turns into a blockage in the mevalonate biosynthetic pathway and in ras protein farnesylation. However, antitumor properties of statins, that have been recently reviewed (Graaf et al. 2004), are quite more complex, and rely on pro-apoptotic, anti-metastatic and anti-angiogenetic effects. Apoptosis induction has been observed on several tumor cell lines, such as acute myelogenous leukemia (AML), juvenile myelomonocytic leukemia, squamous carcinoma of the cervix-uteri, rhabdomyosarcoma, medulloblastoma, mesothelioma, astrocytoma, pancreatic tumor, neuroblastoma and colorectal carcinoma. The growth arrest appears to be p53-independent and is mediated by down-regulation of cdk 2 activity, while the cdk inhibitors p21 and/or p27 are up-regulated (Dulak and Jozkowicz 2005). As combined with butyrate, the compound synergistically suppresses growth of colon carcinoma cells (Caco-2), that are arrested in the G1 phase of the cell cycle after 24 h with a switch to the G2/M phase after 72 h; these effects are accompanied by a down-regulation of cdk 4 and cdk 6, as well as cyclin D1, while cdk 2 and cyclin E levels are stable (Wächtershäuser et al. 2001). Statins may also produce anti-metastatic effects based on a reduced expression of MMP-9 and on a reduced invasiveness that has been experimentally observed on several tumor cell types (Graaf 12 Antitumor compounds from Penicillium. Nicoletti et al. et al. 2004). Although mevastatin have proved to be able to completely block the expression of VEGF in cultured rat primary endothelial cells, and VEGF down-regulation have been observed in several tumor cell types (Jones et al. 1999), the effects of statins on angiogenesis are quite controversial (Graaf et al. 2004). Wortmannin (33), originally isolated from T. wortmanni (anamorph P. kloeckeri or P. wortmanni) (Brian et al. 1957), is a specific and potent inhibitor of the phosphatidylinositol-3-kinase (PI3K), that is bound at the ATP-binding site of its catalytic domain (Arcaro and Wymann 1993; Powis et al. 1994; Ui et al. 1995; Hazeki et al. 1996; Walker et al. 2000). The PI3K/Akt signalling pathway is involved in a large number of fundamental cellular processes, including apoptosis, proliferation, cell motility and adhesion, and its constitutive activation has been implicated in both the pathogenesis and the progression of a wide variety of neoplasiae, and in the malignant transformation of cells. Increased levels of PI3K products have been observed in colorectal tumors and in breast cancers, while their dephosphorylation suppresses tumor formation. Hence, this pathway is an attractive target for the development of novel chemotherapeutic strategies. For example, PI3K/Akt signaling is frequently activated in AML blasts and strongly contributes to proliferation, survival and drug resistance of these cells. Upregulation of the PI3K/Akt network may be due to several reasons, including FLT3, ras or c-kit mutations. Small molecules designed to selectively target key components of this signal transduction cascade induce apoptosis and/or markedly increase sensitivity of AML blasts to conventional drugs. Thus, inhibitory molecules are currently being developed for clinical use either as single agents or in combination with other antitumor pharmaceuticals (Martelli et al. 2006). Further evidence of the antitumor effects of wortmannin results by its ability to inhibit proliferation of KNS-62 and Colo-699 lung cancer cells, by a delayed growth of subcutaneously induced tumors as a consequence of PI3K inhibition occurring prior to xenotransplantation, and by increased survival of human non-small cell lung cancer after intrapulmonary xenotransplantation. However, the systemic toxicity of wortmannin appears to condition its pharmacological applications (Boehle et al. 2002). Cytochalasans are cytostatically active metabolites produced by many and diverse fungal species presenting an isoindolone unit fused to an 11- to 14-membered carbocyclic or heterocyclic lactone or carbonic diester. A marine strain later identified as P. marinum has been reported to produce two series of compounds belonging to such class, penochalasins (Numata et al. 1995; Iwamoto et al. 2001) and penostatins (A-I) (Takahashi et al. 1996; Iwamoto et al. 1998), showing cytotoxic properties against P388 lymphocytes. P. marinum is also a source of other structurally related extrolites, the chaetoglobosins (indolylcytochalasins) (Numata et al. 1995), that are known in P. expansum (Frisvad and Filtenborg 1989) and P. discolor (Frisvad et al. 1997), too. Particularly, chaetoglobosin K (34) has been reported for its antitumor activity in rat glial cells and growth inhibitory effects in ras-transformed NIH 3T3 fibroblasts through a PI3K-mediated pathway (Numata et al. 1995). This effect is quite complex in that the compound suppresses cell growth by inducing overexpression of a gene encoding a large plus-end of a F-actin capping protein called tensin, and has a F-actin capping potential itself; moreover it induces apoptosis by inhibiting the kinase PKB/ Akt (Tikoo et al. 1999). Growth inhibition was also observed in ras-transformed liver epithelial cells (WB-ras1), where treatment with chaetoglobosin K reduced the level of phosphorylation of Akt kinase and cytokinesis (Matesic et al. 2006). Sclerotiorines (or sclerotiorins) and isochromophilones are azaphilone compounds isolated from P. sclerotiorum (synonym P. multicolor) (Curtin and Reilly 1940; Omura et al. 1993; Arai et al. 1995; Matsuzaki et al. 1995; Pairet et al. 1995; Yang et al. 1996). The former have been also found in Eupenicillium spp. (Udagawa 1963), in T. luteus (anamorph P. luteum) (Fujimoto et al. 1990) and in P. glabrum (reported under the synonym P. frequentans: Chidananda et al. 2006). Grb2 is an important adaptor protein in the mitogenic ras signaling pathway of receptor tyrosine kinases, containing one SH2 domain that binds to specific phosphotyrosine residues on receptors or adaptor proteins. SH2 domain antagonists may be developed as new antitumor agents that act by blocking the oncogenic ras signals. Sclerotiorin (35) and isochromophilone IV represent the first non-peptidic inhibitor of the SH2 domain from a natural source that significantly inhibits the binding Grb2-SH2 (Nam et al. 2000b). The analogue 8-O-methylsclerotiorinamine showed the same biological activity (Nam et al. 2000a), while antiproliferative properties on B-16 mouse melanoma cells were evidenced for isochromophilones III, V and VI (Arai et al. 1995). Nine azaphilones designated RP-1551-1, -2, -3, -4, -5, 6, -7, -M1, and -M2 have been extracted from the culture broth of an unidentified Penicillium strain; RP-1551-7 corresponds to luteusin A, previously characterized from T. luteus (Fujimoto et al. 1990). The antitumor effect of these compounds depends on the irreversible inhibition of the binding to its -receptor of the platelet-derived growth factor, which is a potent mitogen molecule for various cell types (Toki et al. 1999). Compound HY558-1 (36) is a hydroxyhydrazinoeicosane isolated from liquid cultures of a strain of P. minioluteum showing cdk 1 inhibitory properties and antiproliferative effects on several human tumor cell lines, such as HepG2 (hepatoma), HeLa, HT-29, HL-60, and AGS (gastric epithelial cells), while low levels of inhibition were observed on A549 (Lee et al. 2002a). In HepG2 and HeLa, cell cycle is arrested at the G1 and G2/M phases, and treated cells show DNA fragmentation as an effect of apoptosis induction (Lee et al. 2002a; Lim et al. 2004). The compound inhibits the phosphorylation of pRb and reduces the expression of cdk 2, cdc2, and cyclin A, while the level of p21 increases. Accordingly, the compound inhibits HeLa cell proliferation through the induction of cell cycle arrest at the G1 phase by inhibiting pRb phosphorylation in consequence of an upregulation of p21, and at the G2/M phase by directly inhibiting cdc2 and cyclin A. Apoptotic induction is associated with the cleavage of Bid and release of cytochrome c from mitochondria into the cytosol. The mitochondrial pathway is primarily involved in the apoptotic process as suggested by the activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase (Lim et al. 2004). Rubratoxin B (37) was originally described as a metabolite of P. rubrum (Townsend et al. 1966), and later detected from a culture filtrate of P. purpurogenum by Natori et al. (1970), who also reported its cytotoxic effect on HeLa cells. Both identifications were later referred to P. crateriforme (Frisvad 1989), a species that is now considered as a synonym of P. rubrum. However, production of this extrolite by P. purpurogenum has been reported again very recently (Wang et al. 2007). Preliminary treatment with rubratoxin B of young rats in which Yoshida ascites sarcoma cells had been injected intraperitoneally produced an increase in the survival of the animals developing neoplasia (Fimiani and Richetti 1993). More recent evidence of antitumor properties of the compound has resulted on account of cytotoxicity and inhibitory activities against MMP-2 and -9 documented on HT1080 cells; in addition, it is able to inhibit at the G2/M phase the cell cycle progression of tsFT210 cells, that is a cdc2 mutant cell line deriving from FM3A particularly sensitive for detecting cdc2 kinase inhibitors (Wang et al. 2007). A similar effect on inhibition of cell cycle progression in tsFT210 cells has been also documented for acetophthalidin (38), isolated from an unidentified strain obtained from a marine sediment sample (Cui et al. 1996b), as well as for verruculogen and fumitremorgin B (39) (Cui et al. 1996a), prenylated indole alkaloids with a diketopiperazine structure produced by several Penicillium species. The structural analogue fumitremorgin C has been characterized 13 International Journal of Biomedical and Pharmaceutical Sciences 2 (1), 1-23 ©2008 Global Science Books Topopyrones are anthraquinone compounds (e.g. topopyrone C, 43) isolated from the culture broth of an unidentified Penicillium strain that proved to be cytotoxic to HeLa cells and several murine tumor cell lines, such as B16 (melanoma), Colon 26 (colon adenocarcinoma), 3LL (lung carcinoma), P388 and L1210. Their activity and selectivity as topoisomerase-inhibitors were comparable to those of camptothecin, a well-known antitumor product. Particularly, they inhibit the relaxation of supercoiled pBR322 DNA by human DNA topoisomerase I, while DNA topoisomerase II is not affected (Kanai et al. 2000). The same mechanism of action has been detected for ergosterol peroxide, extracted by a strain of P. oxalicum, that also showed selective cytotoxicity against human colon carcinoma cells (COLO 205) (Yang Kuo et al. 2005). Other ergosterol derivatives have very recently showed cytotoxic activity: ergosta-8(14),22-diene-3,5,6,7-tetraol from an unidentified strain of marine origin inhibiting HepG (Sun et al. 2006), and 5,8-epidioxy-23-methyl-(22E, 24R)-ergosta6,22-dien-3-ol from a halophilic strain of P. chrysogenum (reported under the synonym P. notatum) that was effective against P388 (Xin et al. 2007b). Other extrolites acting as cell cycle and DNA synthesis inhibitors display a specific action on DNA topoisomerase. Actually, a combination of these properties is considered particularly effective to enhance the final therapeutic outcome of antitumor pharmaceuticals (Rudolf and Cervinka 2003). Epolactaene (44) is a lactam detected in the culture supernatant of an unidentified Penicillium strain (Kakeya et al. 1995). The compound is structurally unstable under light, and more thorough studies have been carried out using synthetic derivatives with a modified alkyl side chain. Actually this part of the molecule interacting with cell membranes is quite important for its biological activity, possibly related to a pro-apoptotic effect that has been experimentally observed in BALL-1, Jurkat and U937 myelomonocytic cells (Nakai et al. 2002). Moreover, arrest of the cell cycle at the G0/G1 phase and promotion of neurite outgrowth were found to be induced in the neuroblastoma cell line SHSY5Y (Kakeya et al. 1997). It has been observed that epolactaene does not intercalate into DNA, but can alter DNA synthesis by inducing selective inhibition of mammalian and DNA polymerase and human DNA topoisomerase II, despite the dissimilarity in both structure and properties of these two enzymes; again the inhibitory action is possibly related to the neuritogenic effect (Mizushina et al. 2000b). Apart the side chain containing a -conjugated (E,E,E)triene, the molecular structure of epolactaene is characterized by a highly oxidized -lactam possessing electrophilic characteristics in its -unsaturated ketone, epoxide, and hemiaminal carbon, which are potentially reactive with biological nucleophiles, such as the sulphydryl function of cysteine residues (Nagumo et al. 2004). In fact, the compound is effective in binding to Hsp60, which is inactivated by alkylation at the Cys442 residue and inhibited in its chaperone activity (Nagumo et al. 2005). Nidulalins, a group of dihydroxanthone derivatives comprising nidulalin A (45), and compounds F390B and F390C, are produced by two different strains of unidentified Penicillium species. They exhibit cytotoxic activity against human (HCT-116, K562) and murine (P388, FM3A/ADR) cell lines (Sato et al. 1997). Nidulalin A and F390B inhibited DNA topoisomerase II, while F390C was more effective in inhibiting DNA topoisomerase I (Sato et al. 2000). Another class of extrolites able to interfere in cell cycle progression is represented by inhibitors of prenylation of ras proteins. Mutant ras oncogenes are associated with carcinogenesis, and modulation of ras function represents a means by which tumor cells with oncogenic mutations can be sensitized to chemotherapy (Waddick and Uckun 1998). Prenylation of ras proteins plays a major role in cell proliferation of both normal and cancerous cells. Normal and oncogenic ras proteins are post-translationally modified by a farnesyl group that promotes membrane binding. Inhibition of farnesyltransferase (FTase), the main enzyme that as a potent and specific chemosensitizing agent able to overcome multidrug resistance in breast cancer (Rabindran et al. 2000). Some structural relationship with tremorgenic extrolites is showed by the shearinines, indole triterpenes isolated for the first time from E. shearii (e.g. shearinine A, 40) (Belofsky et al. 1995). Very recently more analogues have been characterized from a marine-derived strain of P. janthinellum (Smetanina et al. 2007), and from an unidentified endophytic strain related to the latter species (Xu et al. 2007). Shearinines A, D, and E are able to induce apoptosis in HL60 cells; in addition, shearinine E presents cancer preventive properties deriving from the capacity to inhibit malignnant transformation of mouse epidermal JB6 P+ Cl 41 cells (Smetanina et al. 2007). Islandicin and its isomer emodin (41) are anthraquinone compounds produced by P. islandicum and a number of unrelated species. Emodin is known as a specific inhibitor of protein tyrosine kinase p56lck and protein kinase C (Jayasuriya et al. 1992; Fredenhagen et al. 1995), whose deregulation is associated with malignant transformation of tumors. These properties introduce a potential therapeutic use of this compound as an anticancer agent that also relies on its inhibitory effect on cell cycle modulation in specific oncogene overexpressed cells. Antiproliferative effects of emodin on hepatoma cell lines (HepG2/C3A, PLC/PRF/5, SKHEP-1) were consequential to an arrest of the cell cycle at the G2/M phase followed by apoptosis occurring with significant increase in the levels of p53, p21, Fas and caspase-3 (Shieh et al. 2004). On HeLa and other cervix-uteri cell lines (Ca Ski, ME-180 and Bu 25TK) the compound induces inhibition of DNA synthesis, followed by increased nuclear condensation and apoptosis; again the apoptotic pathway is caspase-dependent, as shown by the activation of caspases-3 and -9 and the cleavage of poly(ADP-ribose) polymerase (Srinivas et al. 2003). By its quinone structure emodin may also interfere with the electron transport process and alter the cellular redox status, with ensuing cytotoxic properties. Its possible use in combination with standard drugs to reduce toxicity and to enhance efficacy of chemotherapy has been recently proposed (Srinivas et al. 2007), also considering its inhibitory effects on metastasis and angiogenesis that have been demonstrated both in vitro and in vivo (Kwak et al. 2006). The antitumor activity of biosynthetic derivatives of emodin and of its structural analogue chrysophanol has also been investigated against L1210 and HL-60 cells (Kawai et al. 1984; Darzynkiewicz et al. 1989; Koyama et al. 1989), also with reference to DNA cleavage mediated by topoisomerase II (Kong et al. 1992). Some species producing anthraquinones are also able to synthesize a number of dimers (bis-anthraquinones), such as skyrin, rubroskyrin, luteoskyrin and rugulosin, releasing chrysophanol and/or emodin upon decomposition (Breen et al. 1955; Takeda et al. 1973; Kawai et al. 1984), and also directly exhibiting strong inhibitory effects on the growth of the above-mentioned leukemic cell lines (Kawai et al. 1984; Ueno et al. 1995). Very recently, some more anthraquinone derivatives, mostly known as intermediate in aflatoxin and sterigmatocystin biosynthesis, have been reported from a marine strain of P. flavidorsum (synonym of P. glabrum); these compounds, namely nidurufin, averantin, averufin, versicolorin A and B, versiconol, 8-O-methylaverufin and 6,8-O-dimethylaverufin possess antiproliferative properties against K562 cells, particularly consistent for the first two compounds (Ren et al. 2007). Another anthraquinone compound, MT81 (42), has been reported from a strain of P. nigricans, a species that is now considered a synonym of P. janczewskii. This extrolite determined a remarkable decrease in volume of transplantable murine tumors and viable tumor cell count, more pronounced in sarcoma 180 than in Ehrlich ascites; at the cell level these effects corresponded to a reduction in mitotic activity and apoptotic symptoms, such as the appearance of membrane blebbing and intracytoplasmic vacuoles (Gupta et al. 1997). 14 Antitumor compounds from Penicillium. Nicoletti et al. catalyzes the prenylation of ras proteins, turns into an arrest of growth of tumor cells. In addition, FTase inhibitors may indirectly help in cancer therapy by suppression of angiogenesis and induction of apoptosis (Ayral-Kaloustian and Salaski 2004). Some Penicillium extrolites, such as andrastins and barceloneic acid A, may act as FTase inhibitors (Overy et al. 2005a). Andrastins (A-D) were originally described in an unidentified biverticillate Penicillium strain (Omura et al. 1996; Uchida et al. 1996), and later reported from several terverticillate species, such as P. roqueforti (Nielsen et al. 2005), P. paneum (O’Brien et al. 2006) and P. albocoremium, also producing barceloneic acid A (Overy et al. 2005a). Moreover, andrastin A (46) may directly interact with the trans-membrane glycoprotein (P170), an ABCtransporter involved in multidrug resistance of neoplastic cells, thus enhancing the chemotherapeutic effects of some antitumor agents (Rho et al. 1998). Citreohybridones produced by E. euglaucum (reported under the synonym P. citreoviride: Kosemura et al. 1991; Kosemura 2003) are structurally similar to andrastins and, especially citreohybridone B, also showed FTase inhibitory properties (Omura et al. 1996). Some ras isoforms are also substrates for geranylgeranyltransferase I (GGTase), a related prenyltransferase that can carry on promoting cell proliferation after treatment with selective FTase inhibitors. Therefore a combination of FTase and GGTase inhibitors is required for therapeutic purposes, unless it be possible to use a product with combined properties. This is the case of gliotoxin (47), a widespread mycotoxin belonging to the class of the epipolythiodiketopiperazines, structurally characterized by a bridged disulphide ring which determines its antimicrobial and immunotoxic properties (Waring and Beaver 1996). This extrolite is also produced by some Penicillium species, such as P. corylophilum (Mull et al. 1945: original report as P. obscurum) and P. glabrum (Brian 1946: producing strain originally misidentified as P. terlikowskii). Antitumor properties of gliotoxin are known since over fifty years after its antiproliferative activity was observed on mouse lymphosarcoma and mammary carcinoma cells (Mason and Kidd 1951). After having been ascribed to effects on DNA fragmentation (Braithwaite et al. 1987), its cytostatic activity was more directly referred to FTase inhibition (van der Pyl et al. 1992). More recently antiproliferative effects have been pointed out on six breast cancer cell lines (MCF-7, T47D, BT-474, ZR75-1, MDA MB231 and MDA MB435), with conclusive evidence in favor of prenyltransferase inhibition (Vigushin et al. 2004). However, the compound also exhibits potent direct pro-apoptotic properties that have been reviewed by Waring and Beaver (1996). Furthermore, it has been shown that on HL-60 cells gliotoxin increases the phosphotransferase activities of c-Jun N-terminal kinase1 and p38, and inhibits the transcriptional activating protein AP-1 and NFB (Chung et al. 1998). Apoptosis triggered by gliotoxin is associated with the induction of caspase-3-like proteases (Zhou et al. 2000), following the activation of the pro-apoptotic Bcl-2 family member Bak that is elicited by the generation of reactive oxygen species and the mitochondrial release of apoptogenic factors (Pardo et al. 2006). mitogens for endothelial cells, such as bFGF and VEGF. However, interaction of VEGF with tumorigenesis also involves complex molecular mechanisms, such as the activation of oncogenes and the inactivation of tumor suppressor genes (Xie et al. 2004). Therefore, inhibition of VEGF production and/or its effects on endothelial cells is considered as a main target in cancer therapy. This mechanism of biological activity characterizes the antitumor properties of asterric acid (48) and some derivatives, namely sulochrin, methyl asterric acid, 3-chloroasterric acid and 3,5-dichloroasterric acid, that proved to be able to inhibit VEGF-induced tube formation of human umbilical vein endothelial cells (Lee et al. 2002b). Fumagillin (49) is a sesquiterpene produced by some Penicillium species belonging to the section Divaricatum in the subgenus Furcatum. Its antitumor properties have been reported in correlation to the inhibition of endothelial cell proliferation in vitro and of tumor-induced angiogenesis in vivo (Ingber et al. 1990). These effects are consequential to cell cycle arrest and apoptosis resulting after the inhibition of methionine aminopeptidase type 2, an enzyme that removes the N-terminal methionine from most protein involved in cell cycle regulation (Kwon et al. 2000). The key reactive sites of the molecule are its spiroepoxide structure and side chain epoxide group (Griffith et al. 1998). In a recent review, diketopiperazines are cited as the most potent inhibitors of plasminogen activator inhibitor-1 (PAI-1), whose increased levels are correlated to angiogenesis and metastatic evolution of cancer, as demonstrated by the resistance to invasion and angiogenesis by implanted malignant cells in PAI-1 knockout mice (Martins and Carvalho 2007). Besides possibly characterizing other abovementioned compounds belonging to this class, anti-angiogenic activity has been reported by two diketopiperazine dimers biosynthetically related to gliotoxin, 11,11-dideoxyverticillin A and 11-deoxyverticillin A. These extrolites have been characterized by an unidentified Penicillium strain obtained from the Caribbean green alga Avrainvillea longicaulis, and showed potent cytostatic properties against HCT-116 cells (Son et al. 1999). Particularly, the first compound possesses an antiproliferative effect on human umbilical vein endothelial cells, based on the blockage of their tube formation and the inhibition of the anti-apoptotic and migration inducing effects of VEGF. Moreover, the compound completely blocks VEGF-induced microvessel sprouting from Matrigel-embedded rat aortic rings and vessel growth in Matrigel plugs in mice, and decreases VEGF secretion by MDA MB-468 cells (Chen et al. 2005). Cancer cells must be able to degrade the extracellular matrix in order to become invasive and induce metastatic spread. Metalloproteinase are a family of zinc-dependent peptidases capable of degrading all kinds of extracellular matrix proteins, and playing a major role in cell proliferation, migration (adhesion/dispersion), differentiation and angiogenesis. MMP-inhibitors may therefore have multiple beneficial effects in cancer chemotherapy. Berkeleydione (50) and berkeleytrione are hybrid polyketide-terpenoid compounds characterized as extrolites of an unidentified Penicillium species recovered from the unique environment of the Berkeley Pit Lake in Montana (USA) resulting from a copper mining activity. Both compounds inhibited MMP-3, while berkeleydione also showed a selective activity toward nonsmall cell lung cancer NCIH460 (Stierle et al. 2004). Inhibitory effects on MMP-3 also characterize the spiroketal compound berkelic acid, which has been later recovered from the same strain and showed selective activity toward the ovarian cancer cell line OVCAR-3 (Stierle et al. 2006). An endo--D-glucuronidase, heparanase, is capable of specifically degrading heparan sulphate, one of the components of the extracellular matrix, and this activity is associated with the metastatic potential of tumor cells. Heparanase mRNA is overexpressed in many human tumors, such as hepatomas and esophageal carcinomas (Simizu et al. 2004). Trachyspic acid (51), a polyketide compound iso- ANGIOGENESIS INHIBITORS AND ANTIMETASTATIC COMPOUNDS Angiogenesis is indispensable for solid tumor development and their metastatic progression (Zetter 1998). Antivascular effect is a recognized property of several known antitumor agents, especially the above-considered microtubule-targeted compounds that have been observed to readily induce a reduction of blood flow within solid tumors based on a mechanism of action yet to be understood (Jordan and Wilson 2004). The antiangiogenic effect of other natural products has been better elucidated. In fact, the formation of new blood vessels is mediated by proteins acting as specific 15 International Journal of Biomedical and Pharmaceutical Sciences 2 (1), 1-23 ©2008 Global Science Books lated from the culture broth of T. trachyspermus (anamorph P. lehmanii), has been found to be able to inhibit heparanase in B16BL6 murine melanoma (Shiozawa et al. 1995). Another feature that is significantly correlated with metastatic properties of tumor cells is their ability to grow without a firm substrate attachment. To this regard anicequol (52), an ergosterol derivative produced by P. aurantiogriseum, is able to inhibit the anchorage-independent growth of human colon cancer DLD-1 cells (Igarashi et al. 2002). FUTURE PERSPECTIVES As many as 76 extrolites, or extrolite families comprising several analogue compounds, produced by species in the genus Penicillium have been considered in this review on account of their consistent biological properties that may present useful implications as antineoplastic pharmaceuticals. This number is expected to increase quickly, provided that, besides the likely discovery of novel drugs in the near future, some more known compounds may result to possess effective antitumor properties. In fact, after the recent preliminary evidence provided by the aurantiomides (Xin et al. 2007a), this is probably the case of anacin, auranthine, the verrucines, cyclopeptin and other members of the viridicatol family, produced by several terverticillate species (Larsen et al. 2000), that belong to the benzodiazepines, a class of natural products comprising known anticancer pharmaceuticals (Beurdeley-Thomas et al. 2000). Extrolites representing the janthitrem class, such as paxillin, paspalinine, penitrems, thomitrems and the janthitrems themselves, might also possess some extent of the biological activity exhibited by the related compounds verruculogen and the fumitremorgins. Penisimplicissin, a vermistatin analogue produced by P. simplicissimum (Komai et al. 2006a), and other funicone-like compounds might show some extent of cytostatic properties. Diketopiperazines also represent a widespread class among Penicillium extrolites; besides evidences of cytotoxicity reported for piscarinines A and B from P. piscarium (Kozlovsky et al. 2000c), several known compounds, such as rugulosuvine and other puberulines, or roquefortine and its analogues, are possible candidates for a more thorough evaluation of their biological activity in this particular field. Citreoisocoumarins produced by species such as P. nalgiovense, P. roqueforti (Frisvad et al. 2004) and P. corylophilum (Malmstrøm et al. 2000) might also disclose some antitumor effects as reported in duclauxin and other isocoumarin metabolites. So far the curvularins, polyketide macrolides produced by several taxonomically unrelated species such as P. restrictum (producing strain originally identified as P. gilmanii: Raistrick and Rice 1971), E. euglaucum (reported under the synonym P. citreoviride: Lai et al. 1989) and P. sumatrense (Malmstrøm et al. 2000), have displayed quite a weak cytotoxicity on human tumor cell lines (Zhan et al. 2004) but, as they were previously found to affect mitotic spindle formation in sea urchin embryos (Kobayashi et al. 1988), further investigations concerning their microtubule-targeted effects on human cell lines seem to be advisable. The existence of quite diverse mechanisms of biological activity may also address the search of particular compounds within species-complexes that are known to produce extrolites with the desired properties. Actually a number of studies have been recently published reporting on the oriented search of microbial products, such as heparanase (Ishida et al. 2004) or FTase inhibitors (Iwasaki and Omura 2007). To this regard, the availability of standardized screening methods (Smedsgaard 1997; Larsen et al. 2005) coupled with assays for a quick detection of a given biological activity are expected to provide for a prolific and ongoing finding of extrolites to be submitted to clinical trials for the development of novel antineoplastic pharmaceuticals. EXTROLITES WITH OTHER MECHANISMS OF ANTITUMOR ACTIVITY Cyclopiazonic acid (53) is a terpene mycotoxin produced by several terverticillate species. The compound was found to induce a non-univocal and strictly dose-dependent effect on the mouse EL-4 thymoma cells, as their proliferation was slightly increased at 100-1000 ng/mL but markedly depressed at 5-10 μg/mL (Marin et al. 1996). Visible signs of cell death by apoptosis induced by this compound have been found in the spleen of experimentally treated broilers, consisting in margination of chromatin against the nuclear membrane and shrinkage of lymphoid cells without any inflammatory reaction of the surrounding tissues (Kamala Venkatesh et al. 2005). However, its antitumor properties are more clearly introduced by quite a peculiar biochemical mechanism of action. It is known that cell transformation in tumorigenesis requires the influx of external Ca2+, and in most cases the transformation itself has been found to increase intracytosolic Ca2+; therefore, any interference in this mechanism might reduce tumor progression and represent a consistent target of cancer therapy. Ca2+ homeostasis is also related to apoptosis induction in tumor cells; in fact a reduced Ca2+ level in the endoplasmic reticulum is observed in early preneoplastic cells that undergo apoptosis compared to a higher level in late preneoplastic cells, which are less susceptible to apoptosis. Cyclopiazonic acid is able to bind to the sarcoendoplasmic reticulum Ca2+ ATPase that is actively implied in calcium influx and can therefore interfere in the neoplastic transformation (Rosado et al. 2004). Glucose deprivation occurring in poorly vascularized solid tumors activates the unfolded protein response, that is a stress-signalling pathway in tumor cells associated with the glucose-regulated protein 78 (GRP78), an endoplasmic reticulum chaperone whose induction has been shown to protect against programmed cell death (Reddy et al. 2003). Thus, elevated GRP78 levels are correlated with malignancy, and screening for chaperone modulators may represent a novel strategy in anticancer drug development. Verrucosidin (54), a pyrone-type nonaketide originally characterized from a strain classified as Penicillium verrucosum var. cyclopium (Burka et al. 1983) that later was considered to have been misidentified (Frisvad et al. 2004), is a downregulator of the grp78 gene, inhibiting the expression of the GRP78 promoter under glucose-deprived conditions. As assayed on HT-29 cells, the inhibitory action of verrucosidin and induction of selective cell death were found to be strictly dependent on hypoglycemic conditions, as no cytotoxic effect was observed when a sufficient glucose supply was administered in the growth medium (Park et al. 2007). The same mechanism of action was also previously reported for the analogue compound deoxyverrucosidin (Choo et al. 2005). 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Applied and Environmental Microbiology 32, 441-442 23

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