- Volume 13 Issue 8
DOI QR Code
Effects of Valproic Acid on Proliferation, Apoptosis, Angiogenesis and Metastasis of Ovarian Cancer in Vitro and in Vivo
- Shan, Zhao (Department of Obstetrics and Gynecology, the First Affiliated Hospital of Guangxi Medical University) ;
- Feng-Nian, Rong (Department of Obstetrics and Gynecology, Shandong Qianfoshan Hospital) ;
- Jie, Geng (Department of Reproduction, The 174 Hospital of the PLA) ;
- Ting, Zhou (Department of Obstetrics and Gynecology, Shandong Qianfoshan Hospital)
- Published : 2012.08.31
Inhibitors of histone deacetylase activity are emerging as a potentially important new class of anticancer agents. In this study, we assessed the anticancer effects of valproic acid (VPA) on ovarian cancer in vitro and in vivo. Cultured SKOV3 cells were treated by VPA with different concentrations and time, then the effects on cell growth, cell cycle, apoptosis, and related events were investigated. A human ovarian cancer model transplanted subcutaneously in nude mice was established, and the efficacy of VPA used alone and in combination with diammine dichloroplatinum (DDP) to inhibit the growth of tumors was also assessed. Proliferation of SKOV3 cells was inhibited by VPA in a dose and time dependent fashion. The cell cycle distribution changed one treatment with VPA, with decrease in the number of S-phase cells and increase in G1-phase. VPA could significantly inhibit the growth of the epithelial ovarian cancer SKOV3 cells in vivo without toxic side effects. Treatment with VPA combined with DDP demonstrated enhanced anticancer effects. The result of flow cytometry (FCM) indicated that after VPA in vitro and in vivo, the expression of E-cadherin was increased whereas vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) were decreased. This study suggests that VPA could be a novel attractive agent for treatment of ovarian cancer.
Supported by : Natural Science Foundation of Shandong
- Anderson GD (2002). Children versus adults: pharmacokinetic and adverse-effect differences. Epilepsia, Suppl 3, 53-9.
- Allfrey V G, Faulkner R., Mirsky A E, (1964). Acetylation and Methylation of Histones and Their Possible Role in the Regulation of Rna Synthesis. Proc Natl Acad Sci USA, 51, 786-94. https://doi.org/10.1073/pnas.51.5.786
- Boring C, Squires T, Tong T (1992). Cancer statistics 1992. CA Cancer J Clin, 42, 19-38. https://doi.org/10.3322/canjclin.42.1.19
- Bellarosa D, Bressan A, Bigioni M, et al (2012). SAHA/ Vorinostat induces the expression of the CD137 receptor/ ligand system and enhances apoptosis mediated by soluble CD137 receptor in a human breast cancer cell line. Int J Oncol. doi: 10.3892/ijo.2012.1551. https://doi.org/10.3892/ijo.2012.1551
- BDaud AI, Dawson J, DeConti RC, et al (2009). Potentiation of a topoisomerase I inhibitor, karenitecin, by the histone deacetylase inhibitor valproic acid in melanoma: translational and phase I/II clinical trial. Clin Cancer Res, 7, 2479-87.
- Blaheta R A., Michaelis M., Natsheh I, et al (2007). Valproic acid inhibits adhesion of vincristine- and cisplatin-resistant neuroblastoma tumour cells to endothelium. Br J Cancer, 96, 1699-706. https://doi.org/10.1038/sj.bjc.6603777
- Blaheta RA, Michaelis M, Natsheh I, et al (2007). Valproic acid inhibits adhesion of vincristine- and cisplatin-resistant neuroblastoma tumour cells to endothelium. Br J Cancer, 96, 1699-706. https://doi.org/10.1038/sj.bjc.6603777
- Cinatl JJ, Cinatl .J, Hernáiz Driever P, et al (1997). Sodium valproate inhibits in vivo growth of human neuroblastoma cells. Anticancer Drugs, 8, 958-63. https://doi.org/10.1097/00001813-199711000-00007
- Chou C W, Wu M S, Huang W C, et al (2011). HDAC inhibition decreases the expression of EGFR in colorectal cancer cells. PLoS One, 3, e18087.
- Chen Y, Tsai YH, Tseng SH, (2011). Combined valproic acid and celecoxib treatment induced synergistic cytotoxicity and apoptosis in neuroblastoma cells. Anticancer Res, 6, 2231-9.
- Dreifuss F E, Langer D H, (1988). Side effects of valproate. Am J Med, Suppl 1A, 34-41.
- Dive C, Wyllie AH (1993). Apoptosis and cancer chemotherapy. Cancer Chemotherapy, 4, 21-56.
- Francisco R, Pérez-Perarnau A, Cortés C, et al (2012). Histone deacetylase inhibition induces apoptosis and autophagy in human neuroblastoma cells. Cancer Lett, 1, 42-52.
- Feng L, Pan M, Sun J, et al (2012). Histone deacetylase 3 inhibits expression of PUMA in gastric cancer cells. J Mol Med (Berl). [Epub ahead of print]
- Glaser K B, (2007). HDAC inhibitors: Clinical update and mechanismbased potential. Biochem Pharmacol, 74, 659-71. https://doi.org/10.1016/j.bcp.2007.04.007
- Hede K, (2006). Histone deacetylase inhibitors sit at crossroads of diet, aging, cancer. J Natl Cancer Inst, 9, 377-9.
- Kim M S, Blake M, Baek JH, et al (2003). Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res, 63, 7291-300.
- Leiva M, Moretti S, Soilihi H, et al (2012). Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL. Leukemia, 7, 1630-7.
- Lin CT, Lai HC, Lee HY (2008). Valproic acid resensitizes cisplatin-resistant ovarian cancer cells. Cancer Sci, 6, 1218-26.
- Marks PA, Rifkind RA, Richon VM, et al (2001). Histone deacetylases and cancer: causes and therapies. Nature, 1, 194-202.
- Morkve O, Laerum OD, (1991). Flow cytometric measurement of p53 protein expression and DNA content in paraffinembedded tissue from bronchial carcinomas. Cytometry, 5, 438-444.
- Osuka S, Takano S, Watanabe S, et al (2012). Valproic acid inhibits angiogenesis in vitro and glioma angiogenesis in vivo in the brain. Neurol Med Chir (Tokyo), 4, 186-93.
- Ogryzko VV, Hira TH, Russanova VR, et al (1996). Human fibroblasts commitment to a senescence-like state in response to histone deacetylase inhibitors is cell cycle dependent. Mol Cell Biol, 16, 5210-8. https://doi.org/10.1128/MCB.16.9.5210
- Rodriguez-Menendez V, Gilardini A, Bossi M, et al (2008). Valproate protective effects on cisplatin-induced peripheral neuropathy: an in vitro and in vivo study. Anticancer Res, 1A, 335-42.
- Tumber A, Collins LS, Petersen K D, et al (2007). The histone deacetylase inhibitor PXD101 synergises with 5-fluorouracil to inhibit colon cancer cell growth in vitro and in vivo. Cancer Chemother Pharmacol, 60, 275-83. https://doi.org/10.1007/s00280-006-0374-7
- Vallo S, Xi W, Hudak L, et al (2011). HDAC inhibition delays cell cycle progression of human bladder cancer cells in vitro. Anticancer Drugs, 10, 1002-9.
- Wedel S, Hudak L, Seibel JM, et al (2011). Impact of combined HDAC and MTOR inhibition on adhesion, migration and invasion of prostate cancer cells. Clin Exp Metastasis, 5, 479-91.
- Histone deacetylases as targets for treatment of multiple diseases vol.124, pp.11, 2013, https://doi.org/10.1042/CS20120504
- Chloroquine and Valproic Acid Combined Treatment in Vitro has Enhanced Cytotoxicity in an Osteosarcoma Cell Line vol.14, pp.8, 2013, https://doi.org/10.7314/APJCP.2013.14.8.4651
- Suberoylanilide hydroxamic acid (vorinostat): its role on equine corneal fibrosis and matrix metalloproteinase activity vol.17, pp.14635216, 2013, https://doi.org/10.1111/vop.12129
- Valproic acid inhibits the growth of HeLa cervical cancer cells via caspase-dependent apoptosis vol.30, pp.6, 2013, https://doi.org/10.3892/or.2013.2747
- Suppression of triple-negative breast cancer metastasis by pan-DAC inhibitor panobinostat via inhibition of ZEB family of EMT master regulators vol.145, pp.3, 2014, https://doi.org/10.1007/s10549-014-2979-6
- Trichostatin A-induced Apoptosis is Mediated by Krüppel-like Factor 4 in Ovarian and Lung Cancer vol.15, pp.16, 2014, https://doi.org/10.7314/APJCP.2014.15.16.6581
- Biological Screening of Novel Derivatives of Valproic Acid for Anticancer and Antiangiogenic Properties vol.15, pp.18, 2014, https://doi.org/10.7314/APJCP.2014.15.18.7785
- Histones and Their Modifications in Ovarian Cancer â€“ Drivers of Disease and Therapeutic Targets vol.4, pp.2234-943X, 2014, https://doi.org/10.3389/fonc.2014.00144
- Valproic acid inhibits the proliferation of SHSY5Y neuroblastoma cancer cells by downregulating URG4/URGCP and CCND1 gene expression vol.41, pp.7, 2014, https://doi.org/10.1007/s11033-014-3330-3
- Inhibition of Metastasis and Invasion of Ovarian Cancer Cells by Crude Polysaccharides from Rosa Roxburghii Tratt in Vitro vol.15, pp.23, 2015, https://doi.org/10.7314/APJCP.2014.15.23.10351
- The HDACi Panobinostat Shows Growth Inhibition Both In Vitro and in a Bioluminescent Orthotopic Surgical Xenograft Model of Ovarian Cancer vol.11, pp.6, 2016, https://doi.org/10.1371/journal.pone.0158208
- Valproic acid (VPA) inhibits the epithelial–mesenchymal transition in prostate carcinoma via the dual suppression of SMAD4 vol.142, pp.1, 2016, https://doi.org/10.1007/s00432-015-2020-4
- Genetic and epigenetic heterogeneity of epithelial ovarian cancer and the clinical implications for molecular targeted therapy vol.20, pp.4, 2016, https://doi.org/10.1111/jcmm.12771
- Valproic acid exhibits different cell growth arrest effect in three HPV-positive/negative cervical cancer cells and possibly via inducing Notch1 cleavage and E6 downregulation vol.49, pp.1, 2016, https://doi.org/10.3892/ijo.2016.3508
- Valproic acid inhibits epithelial-mesenchymal transition in renal cell carcinoma by decreasing SMAD4 expression vol.16, pp.5, 2017, https://doi.org/10.3892/mmr.2017.7394