article · Journal of Natural Products
Pancreatic cancer cells often survive in nutrient-poor tumour environments by adapting their metabolism, a tolerance that makes them difficult to treat. A newly identified natural compound, ancistrolikokine E3, isolated from the Congolese liana Ancistrocladus likoko, selectively kills human PANC-1 pancreatic cancer cells when they are starved of nutrients. In tests, the compound displayed potent toxicity in nutrient-deprived environments with a fifty percent preferential cytotoxicity concentration of 2.5 micromolar, while leaving cells unharmed in normal, nutrient-rich media. Beyond causing lethal changes to cell shape, it suppresses cancer cell migration and colony formation in a dose-dependent fashion. Laboratory analyses reveal that the compound acts as an early-stage inhibitor of autophagy, turning off key regulatory proteins and blocking the Akt and mTOR signalling pathways that starved cancer cells rely upon to survive.
Pancreatic cancers frequently thrive within tumour environments that lack sufficient nutrients and oxygen, helping them resist conventional medical therapies. By specifically attacking cancer cells only when they are starved, natural compounds such as ancistrolikokine E3 offer a targeted antiausterity approach that could potentially eliminate aggressive cancer cells without poisoning healthy, well-nourished tissue.
This research identifies ancistrolikokine E3 as a potential lead compound for early-stage oncology drug discovery programmes pursuing antiausterity cancer therapies. The primary potential users are pharmaceutical and biotechnology developers working on pancreatic cancer treatments. Because testing has taken place entirely in laboratory cell cultures, the compound remains at an early discovery stage, far from clinical application.
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PANC-1 human pancreatic cancer cells are characterized by their ability to proliferate aggressively under hypovascular and hypoxic conditions in the tumor microenvironment, displaying a remarkable tolerance to nutrition starvation. 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. The new 5,8'-coupled naphthyldihydroisoquinoline alkaloid ancistrolikokine E<sub>3</sub> (4), isolated from the Congolese liana Ancistrocladus likoko, showed potent preferential cytotoxicity against PANC-1 cells under nutrient-deprived conditions, with a PC<sub>50</sub> value of 2.5 μM, without exhibiting toxicity in normal, nutrient-rich medium. The compound was found to induce dramatic alterations in cell morphology, leading to cell death. Moreover, it inhibited significantly PANC-1 cell migration and colony formation in a concentration-dependent manner. This study on 4 provides the first live evidence of the effect of a naphthyldihydroisoquinoline alkaloid against PANC-1 cells in nutrient-deprived medium. Mechanistic investigations conducted suggest that compound 4 is a potent inhibitor of the activation of the Akt/mTOR pathway. Furthermore, it inhibited the expression levels of the key autophagy regulators Atg5, Atg12, Beclin-1, LC3-I, and LC3-II. The results demonstrated that ancistrolikokine E<sub>3</sub> (4) is a potent early-stage inhibitor of the autophagy pathway in PANC-1 human pancreatic cancer cells. Ancistrolikokine E<sub>3</sub> (4) and related naphthylisoquinoline alkaloids are promising potential lead compounds for anticancer drug development based on the antiausterity strategy.
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DOI: 10.1021/acs.jnatprod.8b00733
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