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

Min Tsang Hsieh, Hao Ping Chen, Chi Cheng Lu, Jo Hua Chiang, Tian Shung Wu, Daih Huang Kuo, Li Jiau Huang, Sheng Chu Kuo, Jai Sing Yang

Research output: Contribution to journalArticle

19 Citations (Scopus)

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).

Original languageEnglish
Pages (from-to)782-794
Number of pages13
JournalInternational Journal of Oncology
Volume45
Issue number2
DOIs
Publication statusPublished - 2014 Aug

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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