RRC ID 44825
Author Ueda JY, Athikomkulchai S, Miyatake R, Saiki I, Esumi H, Awale S.
Title (+)-Grandifloracin, an antiausterity agent, induces autophagic PANC-1 pancreatic cancer cell death.
Journal Drug Des Devel Ther
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.
Volume 8
Pages 39-47
Published 2014-1-1
DOI 10.2147/DDDT.S52168
PII dddt-8-039
PMID 24379655
PMC PMC3872082
MeSH Apoptosis / drug effects* Autophagy / drug effects* Bridged-Ring Compounds / pharmacology Bridged-Ring Compounds / therapeutic use* Cell Line, Tumor Dose-Response Relationship, Drug Humans Pancreatic Neoplasms / drug therapy* Pancreatic Neoplasms / pathology Proto-Oncogene Proteins c-akt / antagonists & inhibitors TOR Serine-Threonine Kinases / antagonists & inhibitors
IF 3.216
Times Cited 30
WOS Category CHEMISTRY, MEDICINAL PHARMACOLOGY & PHARMACY
Resource
Human and Animal Cells