title: (+)-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.
authors.affiliation: Frontier Research Core for Life Sciences, Toyama, Japan ; Institute of Natural Medicine, University of Toyama, Toyama, Japan.
authors.forename: Jun-ya
authors.initials: JY
authors.lastname: Ueda
authors.affiliation: Faculty of Pharmacy, Srinakharinwirot University, Nakhon Nayok, Thailand, Japan.
authors.forename: Sirivan
authors.initials: S
authors.lastname: Athikomkulchai
authors.affiliation: Graduate School of Science and Engineering, University of Toyama, Toyama, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Miyatake
authors.affiliation: Institute of Natural Medicine, University of Toyama, Toyama, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Saiki
authors.affiliation: Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan ; National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Esumi
authors.affiliation: Frontier Research Core for Life Sciences, Toyama, Japan ; Institute of Natural Medicine, University of Toyama, Toyama, Japan.
authors.forename: Suresh
authors.initials: S
authors.lastname: Awale
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001952:Bridged-Ring Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D001952:Bridged-Ring Compounds; C560843:grandifloracin; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: (+)-grandifloracin; PANC-1; antiausterity strategy; nutrient starvation