(+)-Grandifloracin, an antiausterity agent, induces autophagic PANC-1 pancreatic cancer cell death

Abstract

Human pancreatic tumors are known to be highly resistant to nutrient starvation, and this prolongs their survival in the hypovascular (austere) tumor microenvironment. Agents that retard this tolerance to nutrient starvation represent a novel antiausterity strategy in anticancer drug discovery. (+)-Grandifloracin (GF), isolated from Uvaria dac, has shown preferential toxicity to PANC-1 human pancreatic cancer cells under nutrient starvation, with a PC₅₀ value of 14.5 μM. However, the underlying mechanism is not clear. In this study, GF was found to preferentially induce PANC-1 cell death in a nutrient-deprived medium via hyperactivation of autophagy, as evidenced by a dramatic upregulation of microtubule-associated protein 1 light chain 3. No change was observed in expression of the caspase-3 and Bcl-2 apoptosis marker proteins. GF was also found to strongly inhibit the activation of Akt, a key regulator of cancer cell survival and proliferation. Because pancreatic tumors are highly resistant to current therapies that induce apoptosis, the alternative cell death mechanism exhibited by GF provides a novel therapeutic insight into antiausterity drug candidates.

Keywords:

• (+)-grandifloracin
• antiausterity strategy
• PANC-1
• nutrient starvation

Acknowledgments

This work was supported by a grant from the Toyama Support Center for Young Principal Investigators in Advanced Life Sciences, Japan, and a Grant in Aid for Scientific Research (No 24510314) from the Japan Society for the Promotion of Science.

Disclosure

The authors report no conflict of interest in this work.