Animals; Antineoplastic Agents/pharmacology/therapeutic use; Antineoplastic Combined Chemotherapy Protocols; Apoptosis/drug effects/physiology; BH3 Interacting Domain Death Agonist Protein/drug effects/metabolism; Caspase 8/metabolism; Cell Line, Tumor; Cell Survival/drug effects/physiology; Cisplatin/pharmacology/therapeutic use; Cyclin-Dependent Kinase Inhibitor p21/agonists/metabolism; Cytochromes c/drug effects/metabolism; Drug Synergism; Enzyme Inhibitors/pharmacology/therapeutic use; Glutamates/pharmacology/therapeutic use; Guanine/analogs & derivatives/pharmacology/therapeutic use; Histones/drug effects/metabolism; Humans; Mesothelioma/drug therapy; Mice; Mice, Inbred BALB C; Mice, SCID; Mitochondria/drug effects/metabolism; Reactive Oxygen Species/metabolism; Valproic Acid/pharmacology/therapeutic use
[en] PURPOSE: Present chemotherapeutic regimens are marginally efficient in tumor cells being particularly resistant to radiotherapy and/or chemotherapy. We hypothesized that unresponsiveness of tumors to conventional therapeutic agents might be due to inappropriate gene expression resulting from epigenetic modifications and leading to transcriptional silencing. The goal of this study was to evaluate the anticancer effect of a histone deacetylase inhibitor, valproate, on mesothelioma cells in combination with pemetrexed and cisplatin, the usual first-line regimen of chemotherapy for this tumor. Experimental Design and RESULTS: We show that valproate augments apoptosis induced by pemetrexed and cisplatin in mesothelioma cell lines and in tumor cells from patient's biopsies. Onset of apoptosis involves both extrinsic and intrinsic pathways requiring enzymatic activities of caspases 8 and 9, respectively. Valproate but not suberoylanilide hydroxamic acid efficiently stimulates the production of reactive oxygen species. The free radical scavenger N-acetylcysteine inhibits apoptosis, indicating that reactive oxygen species are major mediators of valproate activity. As expected, valproate alone or combined with pemetrexed and cisplatin triggers hyperacetylation of histone H3. Bid protein processing in truncated t-Bid and cytochrome c release from mitochondria are significantly increased in the presence of valproate, providing a mechanistic rationale for improvement of the proapoptotic efficacy of cisplatin and pemetrexed. Finally, valproate when combined with pemetrexed and cisplatin prevents tumor growth in mouse models of epithelioid mesothelioma. CONCLUSIONS: These observations support the potential additional efficacy of valproate in combination with pemetrexed and cisplatin for treatment of malignant mesothelioma.
Valproate, in combination with pemetrexed and cisplatin, provides additional efficacy to the treatment of malignant mesothelioma.
American Association for Cancer Research, Inc. (AACR), Birmingham, United States - Alabama