Abstract 4566A: Effect of the anti-histaminic cyproheptadine on cell cycle of hepatocellular carcinoma cells and its mechanisms

Abstract

Abstract Hepatocellular carcinoma (HCC) is a major cause of cancer deaths worldwide; however, current chemotherapeutic drugs for hepatocellular carcinoma (HCC) are either poorly effective or expensive. The majority of patients can't have good outcomes by taking these drugs. Currently, we had a breakthrough finding in a case report of two patients with advanced HCC. We found one had complete remission of liver tumors, one had decrease of their alpha-fetoprotein levels and that both their lung metastasis had complete remission after the concomitant use of thalidomide and cyproheptadine. In light of a previous study that cyproheptadine affects the cell cycle and impedes leukemia cell growth by suppressing the action of transcription factor of cyclin D, we assume that cyproheptadine is the key factor in this treatment. Therefore, the purpose of this study was to investigate whether cyproheptadine inhibits HCC cell growth by impeding cancer cell cycle and to explore the molecular mechanisms of cyproheptadine-induced cell cycle arrest. First, we confirmed that cyproheptadine had inhibition effect on two HCC cell lines, HepG2 and Huh-7, by cell viability assay. Besides, to explore how cyproheptadine affects HCC cell cycle we analyzed DNA content by flow cytometry and found cell cycle arrest at the G1 to S transition in HepG2 cells and at the S to G2 transition in Huh-7 cells. Finally, we investigated the mechanism of cyproheptadine-induced cell cycle arrest using western blot analysis. Interestingly, our results showed that cyproheptadine promoted P38 activation by phosphorylation than subsequently stabilized P16 and caucused hypophosphorylation of Rb in HepG2 cells. On the other hand, cyproheptadine not only promoted P38 activation but also activated ATM/Chk2 pathway to stabilize P21 in Huh-7 cells. These novel results demonstrated that cyproheptadine suppressed HCC cells through the Non-classical P38 MAP Kinase Functions: Cell Cycle Checkpoints and ATM/Chk2 pathway, and provided a potential treatment option in HCC. Citation Format: Cheng-Da Hsu, Yu-Min Feng, Syue-Yi Chen, Jing-Wen Feng. Effect of the anti-histaminic cyproheptadine on cell cycle of hepatocellular carcinoma cells and its mechanisms. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4566A. doi:10.1158/1538-7445.AM2014-4566A