Study On The Feasibility Of Cancer Therapy With Ad-PUMA

Cancer is one of the most lethal human diseases. It is very necessary to seek for multimodality to improve the outcome of cancer therapy. PUMA (p53 upregulated modulator of apoptosis) is a potent proapoptotic molecule that is rapidly induced in cells following DNA damage. In the present study we investigated whether PUMA adenovirus could suppress the growth of solid tumor cells and sensitize cancer cells to chemotherapeutics. The data showed Ad-PUMA had the significant synergism with the anticancer drugs (cisplatin, paclitaxel and 5-fluorouracil) in esophageal cancer cell lines and enhanced chemotherapeutic efficacy in the other cancer cells of diverse tissue origin. Interestingly, Ad-PUMA was found to inhibit cell growth more efficiently than Ad-p53 in esophageal cancer cells irrespective of the p53 status and in cervix cancer cells independent of HPV infection. In vivo, administration of Ad-PUMA could be more potent inhibitory to tumor growth than Ad-p53. Combinative administration of Ad-PUMA and cDDP inhibited tumor growth more efficient than their respective treatment. Ad-PUMA did not additionally contribute to the distribution of cell cycle in G1, S, G2/M resulting from diverse anticancer drugs. But Ad-PUMA infection facilitated apoptosis induced by anticancer drug treatment. This indicates the more potent inhibitory effect on the cells viability by the combination of Ad-PUMA and anticancer drugs may result from a more abundant apoptosis induction. PUMA can induce Bax oligomerization and activate Caspase9, which triggers apoptosis. Bcl-2 overexpression may suppress partly the growth inhibitory effect of Ad-PUMA on HeLa cells.Ad5 and Ad2 are the most widely applied adenovirus vectors in clinical trials...