title: The novel pterostilbene derivative ANK-199 induces autophagic cell death through regulating PI3 kinase class III/beclin 1/Atg‑related proteins in cisplatin‑resistant CAR human oral cancer cells.
abstract: Pterostilbene is an effective chemopreventive agent against multiple types of cancer cells. A novel pterostilbene derivative, ANK-199, was designed and synthesized by our group. Its antitumor activity and mechanism in cisplatin-resistant CAR human oral cancer cells were investigated in this study. Our results show that ANK-199 has an extremely low toxicity in normal oral cell lines. The formation of autophagic vacuoles and acidic vesicular organelles (AVOs) was observed in the ANK-199-treated CAR cells by monodansylcadaverine (MDC) and acridine orange (AO) staining, suggesting that ANK-199 is able to induce autophagic cell death in CAR cells. Neither DNA fragmentation nor DNA condensation was observed, which means that ANK-199-induced cell death is not triggered by apoptosis. In accordance with morphological observation, 3-MA, a specific inhibitor of PI3K kinase class III, can inhibit the autophagic vesicle formation induced by ANK-199. In addition, ANK-199 is also able to enhance the protein levels of autophagic proteins, Atg complex, beclin 1, PI3K class III and LC3-II, and mRNA expression of autophagic genes Atg7, Atg12, beclin 1 and LC3-II in the ANK-199-treated CAR cells. A molecular signaling pathway induced by ANK-199 was therefore summarized. Results presented in this study show that ANK-199 may become a novel therapeutic reagent for the treatment of oral cancer in the near future (patent pending).
authors.affiliation: School of Pharmacy, China Medical University, Taichung 404, Taiwan, R.O.C.
authors.forename: Min-Tsang
authors.initials: MT
authors.lastname: Hsieh
authors.affiliation: Department of Biochemistry, Tzu Chi University, Hualien 970, Taiwan, R.O.C.
authors.forename: Hao-Ping
authors.initials: HP
authors.lastname: Chen
authors.affiliation: Department of Food Science and Biotechnology, National Chung Hsing University, Taichung 402, Taiwan, R.O.C.
authors.forename: Chi-Cheng
authors.initials: CC
authors.lastname: Lu
authors.affiliation: Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan, R.O.C.
authors.forename: Jo-Hua
authors.initials: JH
authors.lastname: Chiang
authors.affiliation: Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan, R.O.C.
authors.forename: Tian-Shung
authors.initials: TS
authors.lastname: Wu
authors.affiliation: Department of Pharmacy and Graduate Institute of Pharmaceutical Technology, Tajen University, Pingtung 907, Taiwan, R.O.C.
authors.forename: Daih-Huang
authors.initials: DH
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung 404, Taiwan, R.O.C.
authors.forename: Li-Jiau
authors.initials: LJ
authors.lastname: Huang
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung 404, Taiwan, R.O.C.
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
authors.affiliation: Department of Pharmacology, China Medical University, Taichung 404, Taiwan, R.O.C.
authors.forename: Jai-Sing
authors.initials: JS
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D013267:Stilbenes / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: C000594719:ANK-199; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D013267:Stilbenes; C107773:pterostilbene; D019869:Phosphatidylinositol 3-Kinases; D002945:Cisplatin