Valproate, in Combination with Pemetrexed and Cisplatin, Provides Additional Efficacy to the Treatment of Malignant Mesothelioma
- Fabian Vandermeers1,
- Pascale Hubert2,
- Philippe Delvenne2,
- Céline Mascaux3,
- Bogdan Grigoriu4,6,
- Arsène Burny1,
- Arnaud Scherpereel4,5 and
- Luc Willems1,2
- Authors' Affiliations:1Molecular and Cellular Biology, Gembloux Agricultural University (FUSAG), Gembloux, Belgium; 2Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liège (ULg), Liège Belgium; 3Jules Bordet Institute, ULB, Brussels, Belgium; 4Pasteur Institute, INSERM U774, and 5Calmette Hospital, CHRU of Lille and University of Lille II, Lille, France; and 6University of Medicine and Pharmacy, Iasi, Romania
- Requests for reprints:
Luc Willems, National Fund for Scientific Research, Cellular and Molecular Biology laboratory, 13 avenue Maréchal Juin, 5030 Gembloux, Belgium. Phone: 32-0-81-622157, Fax: 32-0-81-613888; E-mail: willems.l{at}fsagx.ac.be.
Abstract
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.
Footnotes
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Grant support: “Fonds National de la Recherche Scientifique” (FNRS), the Télévie, the Belgian Foundation against Cancer, the Sixth Research Framework Programme of the European Union (project INCA LSHC-CT-2005-018704), the “Neoangio” excellence program of the “Direction générale des Technologies, de la Recherche et de l'Énergie” of the Walloon government and the “Action de Recherche Concertée Glyvir” of the “Communauté française de Belgique.”
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted January 14, 2009.
- Received July 1, 2008.
- Revision received December 24, 2008.
