[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.
Disciplines :
Oncology
Author, co-author :
Vandermeers, Fabian ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Hubert, Pascale ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Delvenne, Philippe ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Wagner JC, Sleggs CA, Marchand P. Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br J Ind Med 1960;17: 260-71.
Bianchi C, Giarelli L, Grandi G, Brollo A, Ramani L, Zuch C. Latency periods in asbestos-related mesothelioma of the pleura. Eur J Cancer Prev 1997;6:162-6.
de Klerk NH, Musk AW, Williams V, Filion PR,Whitaker D, Shilkin KB. Comparison of measures of exposure to asbestos in former crocidolite workers from Wittenoom Gorge W, Australia. Am J Ind Med 1996; 30:579-87.
Price B. Analysis of current trends in United States mesothelioma incidence. Am J Epidemiol 1997;145: 211 -8.
Leigh J, Davidson P, Hendrie L, Berry D. Malignant mesothelioma in Australia, 1945 -2000. Am J Ind Med 2002;41:188-201.
Herndon JE, Green MR, Chahinian AP, Corson JM, Suzuki Y, Vogelzang NJ. Factors predictive of survival among337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B. Chest1998;113:723-31.
Sedletska Y, Giraud-Panis MJ, Malinge JM. Cisplatin is a DNA-damaging antitumour compound triggering multifactorial biochemical responses in cancer cells: importance of apoptotic pathways. Curr Med Chem Anti-CancerAgents 2005;5:251 -65.
Solomon B, Bunn PA, Jr. Clinical activity of peme- trexed: a multitargeted antifolate anticancer agent. Future Oncol 2005;1:733-46.
Shih C, Chen VJ, Gossett LS, et al. LY231514, a pyrrolo [2,3-d] pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res 1997; 57:1116-23.
Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21: 2636-44.
Rollins KD, Lindley C. Pemetrexed: a multitargeted antifolate. ClinTher 2005;27:1343-82.
Baylin SB, Ohm JE. Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction? Nat Rev Cancer 2006;6:107-16.
Lund AH, van Lohuizen M. Epigenetics and cancer. Genes Dev 2004;18:2315-35.
Wolffe AP, Hayes JJ. Chromatin disruption and modification. Nucleic Acids Res 1999;27:711 -20.
Iizuka M, Smith MM. Functional consequences of histone modifications. Curr Opin Genet Dev 2003;13: 154-60.
Johnstone RW. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 2002;1:287-99.
Chapman A, Keane PE, Meldrum BS, Simiand J, Vernieres JC. Mechanism of anticonvulsant action of valproate. Prog Neurobiol 1982;19:315-59.
Blaheta RA, Nau H, Michaelis M, Cinatl J, Jr. Val- proate and valproate-analogues: potent tools to fight against cancer. Curr Med Chem 2002;9:1417-33.
Brodie MJ, Dichter MA. Antiepileptic drugs. N Engl JMed1996;334:168-75.
Gottlicher M, Minucci S, Zhu P, et al. Valproicacid defines a novel class of HDAC inhibitors inducingdif- ferentiation of transformed cells. EMBO J 2001;20: 6969-78.
Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 2001;276:36734-41.
Ziauddin MF, Yeow WS, Maxhimer JB, et al. Valproic acid, an antiepileptic drug with histone deacety lase inhibitory activity, potentiates the cytotoxic effect of Apo2L/TRAIL on cultured thoracic cancer cells through mitochondria-dependent caspase activation. Neoplasia 2006;8:446-57.
Richon VM, Emiliani S, Verdin E, et al. A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc Natl Acad Sci U S A1998;95:3003-7.
Krug LM, Curley T, Schwartz L, et al. Potentialrole of histone deacetylase inhibitors in mesothelioma: clinical experience with suberoylanilide hydroxamic acid. Clin Lung Cancer 2006;7:257 -61.
Yi X, Wei W, Wang SY, Du ZY, Xu YJ,Yu XD. Histone deacetylase inhibitor SAHA induces ERa degradation in breast cancer MCF-7 cells by CHIP-mediated ubiq- uitin pathway and inhibits survival signaling. Biochem Pharmacol 2008;75:1697-705.
Rustin P. Mitochondria, from cell death to proliferation. Nat Genet 2002;30:352-3.
Peto J, Decarli A, La Vecchia C, Levi F, Negri E. The European mesothelioma epidemic. BrJ Cancer1999; 79:666-72.
Rusch VW, Piantadosi S, Holmes EC. The role of extrapleural pneumonectomy in malignant pleural mesothelioma. A Lung Cancer Study Group trial. J Thorac Cardiovasc Surg 1991;102:1 -9.
Johansson L, Linden CJ. Aspects of histopatholog- ic subtype as a prognostic factor in 85 pleural meso- theliomas. Chest1996;109:109-14.
Pistolesi M, Rusthoven J. Malignant pleural mesothelioma:update, currentmanagement, and newer therapeutic strategies. Chest2004;126:1318-29.
Cao XX, Mohuiddin I, Ece F, McConkey DJ, SmytheWR. Histone deacetylase inhibitor downregu- lation of bcl-xl gene expression leads to apoptotic cell death in mesothelioma. Am J Respir Cell Mol Biol 2001;25:562-8.
Neuzil J, Swettenham E, Gellert N. Sensitization of mesothelioma toTRAIL apoptosis by inhibition of his- tone deacetylase: role of Bcl-xL down-regulation. Biochem Biophys Res Commun 2004;314:186-91.
Minucci S, Pelicci PG. Histone deacetylase inhibi- tors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 2006;6:38-51.
Spiller HA, Krenzelok EP, Klein-SchwartzW, et al. Multicenter case series of valproic acid ingestion: serum concentrations and toxicity. J Toxicol Clin Toxicol 2000;38:755-60.
Henry TR. The history of valproate in clinical neu- roscience. Psychopharmacol Bull 2003;37 Suppl 2: 5-16.
Rasheed WK, Johnstone RW, Prince HM. Histone deacety lase inhibitors in cancer therapy. Expert Opin InvestigDrugs 2007;16:659-78.
Kelly WK, Richon VM, O'Connor O, et al. Phase I clinical trial of histone deacetylase inhibitor: suberoy- lanilide hydroxamic acid administered intravenously. Clin Cancer Res 2003;9:3578-88.
Hardy JR, Rees EA, Gwilliam B, LingJ, Broadley K, A'Hern R. A phase II study to establish the efficacy and toxicity of sodium valproate in patients with can- cer-related neuropathic pain. JPain Symptom Manage 2001;21:204-9.
Singh G, Driever PH, Sander JW. Cancer risk in people with epilepsy: the role ofantiepileptic drugs. Brain 2005;128:7-17.
Lindemann RK, Gabrielli B, Johnstone RW. Histone-deacetylase inhibitors for the treatment of cancer. Cell Cycle 2004;3:779-88.
Dokmanovic M, Marks PA. Prospects: histone deacetylase inhibitors. J Cell Biochem 2005;96: 293-304.
Marchion DC, Bicaku E, Daud AI, Sullivan DM, Munster PN. Valproic acid alters chromatin structure by regulation of chromatin modulation proteins. Cancer Res 2005;65:3815-22.
Catalano MG, Fortunati N, Pugliese M, et al. Valproic acid, a histone deacetylase inhibitor, enhances sensitivity to doxorubicin in anaplastic thyroid cancer cells. JEndocrinol 2006;191:465-72.
Stewart JH, Tran TL, Levi N, Tsai WS, Schrump DS, Nguyen DM. The essential role of the mitochondria and reactive oxygen species in Cisplatin-mediated enhancement of fas ligand-induced apoptosis in malignant pleural mesothelioma. J Surg Res 2007; 141:120-31.
Wang L, Chanvorachote P, Toledo D, et al. Peroxideis a key mediator of Bcl-2 down-regulation and apopto- sis induction by cisplatin in human lung cancer cells. Mol Pharmacol 2008;73:119-27.
Ramirez JM, Ocio EM, San Miguel JF, Pandiella A. Pemetrexed acts as an antimyeloma agent by provoking cell cycle blockade and apoptosis. Leukemia 2007;21:797 - 804.
Portanova P, Russo T, Pellerito O, et al. The role of oxidative stress in apoptosis induced by the histone deacetylase inhibitor suberoylanilide hydroxamic acid in human colon adenocarcinoma HT-29 cells. Int J Oncol 2008;33:325-31.
Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID bycaspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998;94:491-501.
Luo X, Budihardjo I, Zou H, Slaughter C, Wang X. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 1998;94:481 -90.
Wang X. The expanding role of mitochondria in apoptosis. Genes Dev 2001;15:2922-33.
Lagneaux L, Gillet N, Stamatopoulos B, et al. Valproic acid induces apoptosis in chronic lymphocytic leukemia cells through activation of the death receptor pathway and potentiates TRAIL response. Exp Hematol 2007;35:1527-37.
Insinga A, Monestiroli S, Ronzoni S, et al. Inhibitors of histone deacetylases induce tumor-selective apo- ptosis through activation of the death receptor pathway. Nat Med 2005;11:71 -6.
Ding WX, Ni HM, DiFrancesca D, Stolz DB, Yin XM. Bid-dependent generation of oxygen radicals promotes death receptor activation-induced apoptosis in murine hepatocytes. Hepatology 2004;40:403 -13.
Defoort EN, Kim PM, Winn LM. Valproic acid increases conservative homologous recombination frequency and reactive oxygen species formation: a potential mechanism for valproic acid-induced neural tube defects. Mol Pharmacol 2006;69:1304-10.
Na L, Wartenberg M, Nau H, Hescheler J, Sauer H. Anticonvulsant valproic acid inhibits cardiomyocyte differentiation of embryonic stem cells by increasing intracellular levels of reactive oxygen species. Birth Defects Res AClin MolTeratol 2003;67:174 - 80.
Ide T, Tsutsui H, Hayashidani S, et al. Mitochondrial DNA damage and dysfunction associated with oxidative stress in failinghearts after myocardial infarction. Circ Res 2001;88:529-35.
Stordal B, Davey M. Understanding cisplatin resistance using cellular models. IUBMB Life 2007;59: 696-9.
