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: 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
• Journal: International journal of oncology (Int J Oncol) Vol. 45 Issue 2 Pg. 782-94 (Aug 2014) ISSN: 1791-2423 [Electronic] Greece
• PMID: 24889814 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ANK-199
• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• Membrane Proteins
• Stilbenes
• pterostilbene
• Phosphatidylinositol 3-Kinases
• Cisplatin

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis Regulatory Proteins (metabolism)
• Autophagy (drug effects)
• Beclin-1
• Blotting, Western
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cisplatin (pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Membrane Proteins (metabolism)
• Mouth Neoplasms (metabolism, pathology)
• Oligonucleotide Array Sequence Analysis
• Phosphatidylinositol 3-Kinases (metabolism)
• Polymerase Chain Reaction
• Stilbenes (pharmacokinetics, pharmacology)