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http://dx.doi.org/10.14476/jomp.2011.36.1.011

Apoptotic Effect of Co-Treatment with Valproic Acid and 17AAG on Human Osteosarcoma Cells  

Park, Jun-Young (Department of Oral Anatomy, School of Dentistry, Pusan National University)
Park, Se-Jin (Department of Oral Anatomy, School of Dentistry, Pusan National University)
Kim, In-Ryoung (Department of Oral Anatomy, School of Dentistry, Pusan National University)
Park, Bong-Soo (Department of Oral Anatomy, School of Dentistry, Pusan National University)
Jeong, Sung-Hee (Department of Oral Medicine, School of Dentistry, Pusan National University)
Ko, Myung-Yun (Department of Oral Medicine, School of Dentistry, Pusan National University)
Ahn, Yong-Woo (Department of Oral Medicine, School of Dentistry, Pusan National University)
Publication Information
Journal of Oral Medicine and Pain / v.36, no.1, 2011 , pp. 11-20 More about this Journal
Abstract
Valproic acid (VPA) is a well-known anticonvulsive agent and has been used in the treatment of epilepsy for almost 30 years. VPA emerged in 1997 as an antineoplastic agent. And it is known that antitmor activity of VPA is associated with its targeted at histone deacetylases. 17AAG, Inhibition of HSP90 leads to the proteasome degradation of the HSP90 client proteins, such as Akt, Raf/Ras, Erk, VEGF, cyclin D and p53, and causes potent antitumor activity. It is reported that 17AAG-induced HSP90 inhibition results in prevention of cell proliferation and induction of apoptosis in several types of cancer. This study was undertaken to investigate the synergistic apoptotic effect of co-treatment with the histone deacetylases inhibitor, VPA and the HSP90 inhibitor, 17AAG on human osteosarcoma (HOS) cells. Cell viability was evaluated by trypan-blue exclusion. Induction and augmentation of apoptosis were confirmed by Hoechst staining, flow cytometry (DNA hypoploidy and MMP change), Westen blot analysis and immunofluorescent staining. In this study, HOS cells co-treated with VPA and 17AAG showed several lines of apoptotic manifestation such as nuclear condensations, the reduction of MMP, the decrease of DNA content, the release of cytochrome c into cytosol, the translocation of AIF onto nuclei, and activation of caspase-3, caspase-7 and PARP whereas each single treated HOS cells did not. Although the single treatment of 1 mM VPA or 0.5 ${\mu}M$ 17AAG for 48 h did not induce apoptosis, the co-treatment with them induced prominently apoptosis. Therefore our data in this study provide the possibility that combination therapy with VPA and 17AAG could be considered as a novel therapeutic strategy for human osteosarcoma.
Keywords
Apoptosis; Valproic acid; 17AAG; Human osteosarcoma;
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1 Acehan D, Jiang X, Morgan DG, Heuser JE, Wang X, Akey CW. Three-dimensional structure of the apoptosome: Implications for assembly, procaspase-9 binding, and activation. Mol Cell 2002;9:423-432.   DOI   ScienceOn
2 Marks PA, Richon VM, Rifkind RA. Histone deacetylase inhibitors: induces of differentiation or apoptosis of transformed cells. J Natl Cancer Inst 2000;92:1210-1216.   DOI   ScienceOn
3 Kim MS, Kwon HJ, Lee YM, Baek JH, Jang JE, Lee SW, Moon EJ, Kim HS, Lee SK, Chung HY, Kim CW, Kim KW. Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 2001;7:437-443.   DOI   ScienceOn
4 Golab J, Stoklosa T, Czajka A, Dabrowska A, Jakobisiak M, Zagozdzon R, Wojcik C, Marczak M, Wilk S. Synergistic antitumor effects of a selective proteasome inhibitor and TNF in mice. Anticancer Res 2000;20:1717-1721.
5 Wagenknecht B, Hermisson M, Groscurth P, Liston P, Krammer PH, Weller M. Proteasome inhibitorinduced apoptosis of glioma cells involves the processing of multiple caspases and cytochrome c release. J Neurochem 2000;75:2288-2297.
6 Marshansky V, Wang X, Bertrand R, Luo H, Duguid W, Chinnadurai G, Kanaan N, Vu MD, Wu J. Proteasomes modulate balance among proapoptotic and antiapoptotic Bcl-2 family members and compromise functioning of the electron transport chain in leukemic cells. J Immunol 2001;166:3130-3142.   DOI
7 Kwon HJ, Kim MS, Kim MJ, Nakajima H, Kim KW. Histone deacetylase inhibitor FK228 inhibits tumor angiogenesis. Int J Cancer 2002;97:290-296.   DOI   ScienceOn
8 Deroanne CF, Bonjean K, Servotte S, Devy L, Colige A, Clausse N, Blacher S, Verdin E, Foidart JM, Nusgens BV and Castronovo V. Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling. Oncogene 2002;21: 427-436.   DOI   ScienceOn
9 Marks PA, Rifkind RA. Erythroleukemic differentiation. Annu Rev Biochem 1978;47:419-448.   DOI   ScienceOn
10 Dauglas E, Susin SA, Zamzami N, Ferri KF, Irinopoulou T, Larochette N, Prevost MC, Leber B, Andrews D, Penninger J, Kroemer G. Mitochondrionuclear translocation of AIF in apoptosis and necrosis. FASEB J 2000;14:729-739.   DOI
11 Mongan NP, Gudas LJ. Valproic acid, in combination with all-trans retinoic acid and 5-aza-2'- deoxycytidine, restores expression of silenced RARbeta2 in breast cancer cells. Mol Cancer Ther 2005;4:477-486.
12 Karkoulis PK, Stravopodis DJ, Margaritis LH, Voutsinas GE. 17-Allylamino-17-demethoxygeldanamycin induces downregulation of critical Hsp90 protein clients and results in cell cycle arrest and apoptosis of human urinary bladder cancer cells. BMC cancer 2010;10:481-495.   DOI
13 Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999;397:441-446.   DOI   ScienceOn
14 Green DR, Reed JC. Mitochondria and apoptosis. Science 1998;281:1309-1312.   DOI
15 Golab J, Stoklosa T, Czajka A, Dabrowska A, Jakobisiak M, Zagozdzon R, Wojcik C, Marczak M, Wilk S. Synergistic antitumor effects of a selective proteasome inhibitor and TNF in mice. Anticancer Res 2000;20:1717-1721.
16 Witt O, Schweigerer L, Driever PH, Wolff J, Pekrun A. Valproic acid treatment of glioblastoma multiforme in a child. Pediatr Blood Cancer 2004;43:181.   DOI   ScienceOn
17 Warrell RP Jr, He LZ, Richon V, Calleja E, Pandolfi PP. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natl Cancer Inst 1998;90: 1621-1625.   DOI
18 Graziani G, Tentori L, Portarena I, Vergati M, Navarra P. Valproic acid increases the stimulatory effect of estrogens on proliferation of human endometrial adenocarcinoma cells. Endocrinology 2003;144:2822-2828.   DOI   ScienceOn
19 Li XN, Shu Q, Su JM, Perlaky L, Blaney SM, Lau CC. Valproic acid induces growth arrest, apoptosis, and senescence in medulloblastomas by increasing histone hyperacetylation and regulating expression of p21Cip1, CDK4, and CMYC. Mol Cancer Ther 2005;4:1912-1922.   DOI   ScienceOn
20 Takai N, Desmond JC, Kumagai T, Gui D, Said JW, Whittaker S, Miyakawa I, Koeffler HP. Histone deacetylase inhibitors have a profound antigrowth activity in endometrial cancer cells. Clin Cancer Res 2004;10:1141-1149.   DOI   ScienceOn
21 Seki K, Yoshikawa H, Shiiki K, Hamada Y, Akamatsu N, Tasaka K. Cisplatin (CDDP) specifically induces apoptosis via sequential activation of caspase-8, 3 and -6 in osteosarcoma. Cancer Chemother Pharmacol 2000;45:199-206.   DOI   ScienceOn
22 Villa R, Folini M, Porta CD, Valentini A, Pennati M, Daidone MG, Zaffaroni N. Inhibition of telomerase activity by geldanamycin and 17-allylamino, 17- demethoxygeldanamycin in human melanoma cells. Carcinogenesis 2003;24:851-859.   DOI
23 Kieslich M, Schwabe D, Cinatl J Jr, Driever PH. Increase of fetal hemoglobin synthesis indicating differentiation induction in children receiving valproic acid. Pediatr Hematol Oncol 2003;20:15-22.   DOI
24 Lu Y, Yagi T. Apoptosis of human tumor cells by chemotherapeutic anthracyclines is enhanced by Bax overexpression. J Radiat Res(Tokyo) 1999;40:263-272.   DOI   ScienceOn
25 Fellenberg J, Mau H, Nedel S, Ewerbeck V, Debatin KM. Drug-induced apoptosis in osteosarcoma cell lines is mediated by caspase activation independent of CD95-receptor/ligand interaction. J Orthop Res 2000;18:10-17.   DOI   ScienceOn
26 Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999;397:441-446.   DOI   ScienceOn
27 Orlowski RZ. The role of the ubiquitin-proteasome pathway in apoptosis. Cell Death Differ 1999;6: 303-313.   DOI   ScienceOn
28 Gazitt Y, Kolaparthi V, Moncada K, Thomas C, Freeman J. Targeted therapy of human osteosarcoma with 17AAG or rapamycin: characterization of induced apoptosis and inhibition of mTOR and Akt/MAPK/ Wnt pathways. Int J Oncol 2009;34:551-561.
29 Williams GT. Programmed cell death: Apoptosis and oncogenesis. Cell 1991;65:1097-1098.   DOI   ScienceOn
30 Yuan J. Evolutionary conservation of a genetic pathway of programmed cell death. J Cell Biochem 1996;60:4-11.   DOI
31 Babchia N, Calipel A, Mouriaux F, Faussat AM, Mascarelli F. 17-AAG and 17-DMAG-induced inhibition of cell proliferation through B-Raf downregulation in WT B-Raf-expressing uveal melanoma cell lines. Invest Ophthalmol Vis Sci 2008;49: 2348-2356.   DOI   ScienceOn
32 Gurvich N, Tsygankova OM, Meinkoth JL, Klein PS. Histone deacetylase is a target of valproic acidmediated cellular differentiation. Cancer Res 2004;64: 1079-1086.   DOI   ScienceOn
33 Blaheta RA, Cinatl J Jr. Anti-tumor mechanisms of valproate: a novel role for an old drug. Med Res Rev 2002;22:492-511.   DOI   ScienceOn
34 Cinatl J Jr, Kotchetkov R, Blaheta R, Driever PH, Vogel JU, Cinatl J. Induction of differentiation and suppression of malignant phenotype of human neuroblastoma BE(2)-C cells by valproic acid: enhancement by combination with interferon-alpha. Int J Oncol 2002;20:97-106.
35 Kramer OH, Zhu P, Ostendorff HP, Golebiewski M, Tiefenbach J, Peters MA, Brill B, Groner B, Bach I, Heinzel T, Gottlicher M. The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J 2003;22:3411-3420.   DOI
36 De Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 2003;370:737-749.   DOI   ScienceOn
37 Cinatl J Jr, Cinatl J, Driever PH, Kotchetkov R, Pouckova P, Kornhuber B, Schwabe D. Sodium valproate inhibits in vivo growth of human neuroblastoma cells. Anticancer Drugs 1997;8:958-963.   DOI   ScienceOn