A team of researchers from Japan, Germany and the Democratic Republic of the Congo has identified an alkaloid compound in a Congolese species of liana that inhibits the survival of pancreatic cancer cells under nutrient-deprived conditions.
Ancistrocladus sp. Image credit: Eigenes Werk / CC BY-SA 3.0.
Human pancreatic cancer cells are known to proliferate rapidly and aggressively, causing a chronic deficiency of essential nutrients and oxygen due to their high metabolic need, combined with inefficient vascular supply.
Thus, in contrast to normal tissues, the microenvironment of pancreatic tumors is characterized by low levels of nutrients and oxygen.
The ability of pancreatic cancer cells to tolerate these extreme conditions, by displaying a remarkable resistance to starvation, is referred to as ‘austerity.’
The antiausterity strategy is a new approach in anticancer drug discovery aiming at the identification of potent agents that inhibit preferentially the survival of tumor cells during a limited supply of nutrients and oxygen.
“Pancreatic cancer is one of the deadliest forms of cancer, with a 5-year survival rate of less than 5%,” said University of Toyama’s Professor Suresh Awale, Professor Gerhard Bringmann of the Julius-Maximilians-Universität Würzburg and co-authors.
“Because these cancer cells proliferate so aggressively, they deplete nutrients and oxygen in the region of the tumor.”
“Whereas most cells would die under these extreme conditions, pancreatic cancer cells survive by activating a cell signaling pathway called Akt/mTOR.”
“Some researchers are therefore looking for compounds with antiausterity properties that disrupt this pathway. Substances that are preferably toxic to cancer cells under nutrient deprived conditions are called antiausterity compounds.”
Proposed mechanism of action of ancistrolikokine E3 against PANC-1 human pancreatic cancer cells. Image credit: Awal et al, doi: 10.1021/acs.jnatprod.8b00733.
The scientists isolated and characterized a new antiausterity compound from the twigs of the Congolese liana Ancistrocladus likoko.
Named ancistrolikokine E3, the new molecule is an alkaloid, a class of naturally occurring compounds containing nitrogen.
The compound showed potent preferential cytotoxicity against pancreatic cancer cells under nutrient-deprived conditions.
It induced dramatic alterations in cell morphology, leading to cell death. Moreover, it inhibited significantly migration of pancreatic cancer cells and colony formation in a concentration-dependent manner.
“Ancistrolikokine E3 worked by inhibiting the Akt/mTOR pathway,” the researchers said.
“It is a promising compound for anticancer drug development based on the antiausterity strategy.”
The team’s work is published in the Journal of Natural Products.
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Suresh Awal et al. 2018. Ancistrolikokine E3, a 5,8′-Coupled Naphthylisoquinoline Alkaloid, Eliminates the Tolerance of Cancer Cells to Nutrition Starvation by Inhibition of the Akt/mTOR/Autophagy Signaling Pathway. J. Nat. Prod 81 (10): 2282-2291; doi: 10.1021/acs.jnatprod.8b00733
