Journal of Shandong University (Health Sciences) ›› 2020, Vol. 58 ›› Issue (4): 110-117.doi: 10.6040/j.issn.1671-7554.0.2019.1280

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Correlation between valproic acid exposure and cancer risk in epileptic population

WANG Zhendong, DING Wenwen, FENG Zhihui   

  1. Department of Occupational and Environmental Health, School of Public Health, Shandong University, Jinan 250012, Shandong, China
  • Published:2022-09-27

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Abstract: Objective To explore the relationship between valproic acid(VPA)exposure and cancer risk in epileptic population. Methods Patients with epilepsy from 2012 to 2017 were collected from Shandong Multi-Center Healthcare Big-Data. Total incidence of cancer in VPA exposed and unexposed groups were analyzed, and the relative risk(RR)was calculated. The Hazard ratio(HR)was analyzed with Cox model. Correlations between cancer risk and duration of VPA exposure(D)and prescription dose of VPA exposure(P)were analyzed. Results A total of 3 107 people with epilepsy were collected, including 1 233 VPA exposed and 1 788 unexposed. Cancer was detected in 27 and 23 cases in the exposed and unexposed groups, respectively, and the total incidence of cancer was 9.68/1 000(6.03-13.33/1 000)person/year, and 5.70/1 000(3.37-8.03/1000)person/year, respectively. After exposures to carbamazepine, phenobarbital and phenytoin were excluded, the total incidence of cancer in VPA exposed and unexposed group was 4.95/1 000(0.10-9.80/1 000)person/year, and 5.25/1 000(2.15-8.35/1 000)person/year, respectively. After age was adjusted, the RR was 0.79(0.26-2.40), P=0.681. After Cox model was adjusted, HR was 0.80(0.25-2.53), P=0.702. For population with high VPA exposure(D≥100 and P≥10), the incidence of cancer significantly decreased with the increase of duration of exposure(P=0.031). After grouping based on the median duration of VPA exposure, the adjusted HR was 0.59(0.22-1.59), P=0.301. After grouping based on the median of the prescription dose of VPA, the adjusted HR was 0.93(0.35-2.47), P=0.890. Conclusion VPA is not associated with a significant reduction in cancer risk.

Key words: Epilepsy, Valproic acid, Cancer, Hazard ratio

CLC Number: 

  • R730.1
[1] GBD 2016 Epilepsy Collaborators. Global, regional, and national burden of epilepsy, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016 [J]. Lancet Neurol, 2019, 18(4): 357-375.
[2] 陈阳美, 金永寿, 李宇杰. 抗癫痫药的“一线主力”[J]. 家庭医药, 2012, 2012(9): 22-25.
[3] Peraino C, Fry RJ, Staffeldt E. Reduction and enhancement by phenobarbital of hepatocarcinogenesis induced in the rat by 2-acetylaminofluorene [J]. Cancer Res, 1971, 31(10): 1506-1512.
[4] Peraino C, Fry RJ, Staffeldt E. Brief communication: Enhancement of spontaneous hepatic tumorigenesis in C3H mice by dietary phenobarbital [J]. J Natl Cancer Inst, 1973, 51(4): 1349-1350.
[5] Diwan BA, Henneman JR, Nims RW. Enhancement of N-nitrosodiethylamine-initiated hepatocarcinogenesis by phenytoin in male F344/NCr rats at a dose causing maximal induction of CYP2B [J]. Int J Toxicol, 2001, 20(2): 81-87.
[6] Mawatari T, Ninomiya I, Inokuchi M, et al. Valproic acid inhibits proliferation of HER2-expressing breast cancer cells by inducing cell cycle arrest and apoptosis through Hsp70 acetylation [J]. Int J Oncol, 2015, 47(6): 2073-2081.
[7] Luo Y, Wang H, Zhao X, et al. Valproic acid causes radiosensitivity to breast cancer cells via disrupting DNA repair pathway [J]. Toxicol Res(Camb), 2016, 5(3): 859-870.
[8] Romain B, Benbrika-Nehmar R, Marisa L, et al. Histone hypoacetylation contributes to CXCL12 downregulation in colon cancer: impact on tumor growth and cell migration [J]. Oncotarget, 2017, 8(24): 38351-38366.
[9] Liu G, Wang H, Zhang F, et al. The effect of VPA on increasing radiosensitivity in osteosarcoma cells and primary-culture cells from chemical carcinogen-induced breast cancer in rats [J]. Int J Mol Sci, 2017, 18(5): 1027.
[10] Shoji M, Ninomiya I, Makino I, et al. Valproic acid, a histone deacetylase inhibitor, enhances radiosensitivity in esophageal squamous cell carcinoma [J]. Int J Oncol, 2012, 40(6): 2140-2146.
[11] Sun L, He Q, Tsai C, et al. HDAC inhibitors suppressed small cell lung cancer cell growth and enhanced the suppressive effects of receptor-targeting cytotoxins via upregulating somatostatin receptor II [J]. Am J Transl Res, 2018, 10(2): 545-553.
[12] Sanaei M, Kavoosi F, Roustazadeh A, et al. In vitro effect of the histone deacetylase inhibitor valproic acid on viability and apoptosis of the PLC/PRF5 human hepatocellular carcinoma cell line [J]. Asian Pac J Cancer Prev, 2018, 19(9): 2507-2510.
[13] Riva G, Cilibrasi C, Bazzoni R, et al. Valproic acid inhibits proliferation and reduces invasiveness in glioma stem cells through Wnt/β catenin signalling activation [J]. Genes(Basel), 2018, 9(11): 522.
[14] Terranova-Barberio M, Roca MS, Zotti AI, et al. Valproic acid potentiates the anticancer activity of capecitabine in vitro and in vivo in breast cancer models via induction of thymidine phosphorylase expression [J]. Oncotarget, 2016, 7(7): 7715-7731.
[15] Ryu CH, Yoon WS, Park KY, et al. Valproic acid downregulates the expression of MGMT and sensitizes temozolomide-resistant glioma cells [J]. J Biomed Biotechnol, 2012, 2012: 1-9.
[16] Ecke I, Petry F, Rosenberger A, et al. Antitumor effects of a combined 5-aza-2’deoxycytidine and valproic acid treatment on rhabdomyosarcoma and medulloblastoma in Ptch mutant mice [J]. Cancer Res, 2009, 69(3): 887-895.
[17] Duenas-Gonzalez A, Candelaria M, Perez-Plascencia C, et al. Valproic acid as epigenetic cancer drug: preclinical, clinical and transcriptional effects on solid tumors [J]. Cancer Treat Rev, 2008, 34(3): 206-222.
[18] Roffman CE, Buchanan J, Allison GT. Charlson comorbidities index [J]. J Physiother, 2016, 62(3): 171.
[19] Quan H, Li B, Couris CM, et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries [J]. Am J Epidemiol, 2011, 173(6): 676-682.
[20] Kang H, Gillespie TW, Goodman M, et al. Long-term use of valproic acid in US veterans is associated with reduced risk of smoking-related cases of head and neck cancer [J]. Cancer, 2014, 120(9): 1394-1400.
[21] Farwell WR, Scranton RE, Lawler EV, et al. The association between statins and cancer incidence in a veterans population [J]. J Natl Cancer Inst, 2008, 100(2): 134-139.
[22] Sang Z, Sun Y, Ruan H, et al. Anticancer effects of valproic acid on oral squamous cell carcinoma via SUMOylation in vivo and in vitro [J]. Exp Ther Med, 2016, 12(6): 3979-3987.
[23] Singh G, Bell GS, Driever PH, et al. Cancer risk in people with epilepsy using valproate-sodium [J]. Acta Neurol Scand, 2012, 125(4): 234-240.
[24] Hallas J, Friis S, Bjerrum L, et al. Cancer risk in long-term users of valproate: a population-based case-control study [J]. Cancer Epidemiol Biomarkers Prev, 2009, 18(6): 1714-1719.
[25] Lin CC, Hsieh TC, Wu LS. Long-term use of valproic acid and the prevalence of cancers in bipolar disorder patients in a Taiwanese population: An association analysis using the National Health Insurance Research Database(NHIRD)[J]. J Affect Disord, 2018, 232: 103-108.
[26] Eckschlager T, Plch J, Stiborova M, et al. Histone deacetylase inhibitors as anticancer drugs [J]. Int J Mol Sci, 2017, 18(7): 1414.
[27] Singh G, Driever PH, Sander JW. Cancer risk in people with epilepsy: the role of antiepileptic drugs [J]. Brain, 2005, 128(Pt 1): 7-17.
[28] Salminen JK, Tammela TL, Auvinen A, et al. Antiepileptic drugs with histone deacetylase inhibition activity and prostate cancer risk: a population-based case–control study [J]. Cancer Causes Control, 2016, 27(5): 637-645.
[29] Göttlicher M, Minucci S, Zhu P, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells [J]. EMBO J, 2001, 20(24): 6969-6978.
[30] Hsieh LP, Huang CY. Antiepileptic drug utilization in Taiwan: Analysis of prescription using National Health Insurance database [J]. Epilepsy Res, 2009, 84(1): 21-27.
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