Journal of Shandong University (Health Sciences) ›› 2018, Vol. 56 ›› Issue (3): 48-53.doi: 10.6040/j.issn.1671-7554.0.2017.164

Previous Articles    

Valproic acid augments the anti-tumor potential of metformin in PC-3 cells

MAO Shaowei, LU Guoliang, LI Liang, XIA Qinghua   

  1. Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250014, Shandong, China
  • Received:2017-02-23 Published:2022-09-27

PDF (PC)

28

Abstract: Objective To explore the anti-tumor effect of valproic acid(VPA)and metformin on human prostate cancer cells. Methods PC-3 cells were treated with VPA and metformin andmetformin+VPA, and were devided into control group, VPA group, Met group and VPA+MET group. The cell viability and invasion properties were detectedwith CCK-8 and Transwell assay, respectively. Related proteins including pAkt, pSmad3, aH3 and aH4 were detected with Western blotting. Results Both VPA and metformin could inhibit tumor cell migration and viability. Metformin+VPA had much stronger anticancer effect than metformin and VPA alone. Compared with control group and MET group, the VPA+MET group showed induced levels of Akt, pmTOR and pSmad3, but elevated levels of aH3 and aH4. Conclusion The metformin+VPA combination has advantage over metformin mono-treatment in vitro. The regulation of transforming growth factor-β(TGF-β)and mammalian target of rapamycin(mTOR)pathways and the responsiveness of aH3 and aH4 might be involved in this process.

Key words: Prostate cancer, Valproicacid, Metformin, Transforming growth factor-β, Mammalian target of rapamycin

CLC Number: 

  • R737.25
[1] Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015[J]. CA Cancer J Clin, 2016, 66(2): 115-132.
[2] Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014[J]. CA Cancer J Clin, 2014, 64(1): 9-29.
[3] Van De Voorde L, Janssen L, Larue R, et al. Can metformin improve ‘the tomorrow’ of patients treated for oesophageal cancer?[J]. Eur J Surg Oncol, 2015, 41(10): 1333-1339.
[4] Raval AD, Thakker D, Vyas A, et al. Impact of metformin on clinical outcomes among men with prostate cancer: a systematic review and meta-analysis[J]. Prostate Cancer Prostatic Dis, 2015,18(2):110-121.
[5] Incárová L, Zdráhal Z, Fajkus J. New perspectives of valproicacid in clinical practice[J]. Expert Opin Investig Drugs, 2013, 22(12): 1535-1547.
[6] Juengel E, Makarevic J, Tsaur I, et al. Resistance after chronic application of the HDAC- inhibitor Valproic acid is associated with elevated Akt activation in renal cell carcinoma in vivo[J]. PLoS One, 2013, 8(1): e53100.
[7] Hager M, Haufe H, Lusuardi L, et al. PTEN, pAKT, and pmTOR expression and subcellular distribution in primary renal cell carcinomas and their metastases[J]. Cancer Invest, 2011, 29(7): 427-438.
[8] Xie W, Aisner S, Baredes S, et al. Alterations of smadexpression and activation in defining 2 subtypes of human head and neck squamous cell carcinoma[J]. Head Neck, 2013, 35(1): 76-85.
[9] Shlomai G, Neel B, Leroith D, et al. Type 2 Diabetes mellitus and cancer: the role of pharmacotherapy[J]. J Clin Oncol, 2016, 34(35): 4261-4269.
[10] 冯瑾, 陈光侠, 费素娟.二甲双胍抗肿瘤机制的研究进展[J].实用药物与临床, 2016, 19(10): 1310-1315. FENG Jin, CHEN Guangxia, FEI Sujuan. Research progress in anti-tumor effect of metformin[J]. Pratical and Clinical Drugs, 2016, 19(10): 1310-1315.
[11] 王涛,王峰,何炜,等.二甲双胍对人食管癌KYSE450细胞系增殖和凋亡的影响[J].郑州大学学报(医学版), 2015, 50(3): 305-309. WANG Tao, WANG Feng, HE Wei, et al. Effects of metformin on proliferation and apoptosis of human esophageal cancer cells KYSE450[J]. Journal of Zhengzhou University(Medical Sciences), 2015, 50(3): 305-309.
[12] 张涛, 石琦, 金迅波.二甲双胍增强膀胱癌5637细胞对TRAIL的敏感性及其机制研究[J/CD].泌尿外科杂志,2014(1): 21-25. ZHANG Tao, SHI Qi, JIN Xunbo. Metformin sensitizes bladder cancer cells 5637 to TRAIL-induced apoptosis[J]. Journal of Urology for Clinician(Electronic Version), 2014(1): 21-25.
[13] Kato H, Sekine Y, Furuya Y, et al. Metformin inhibits the proliferation of human prostate cancer PC-3 cells via the downregulation of insulin-like growth factor 1 receptor[J]. Biochem Biophys Res Commun, 2015, 461(1): 115-121.
[14] Chen X, Li C, He T, et al. Metformin inhibits prostate cancer cell proliferation, migration, and tumor growth through upregulation of PEDF expression[J]. Cancer Biol Ther, 2016, 17(5): 507-514.
[15] Chen L, Ahmad N, Liu X. Combining p53 stabilizers with metformin induces synergistic apoptosis through regulation of energy metabolism in castration-resistant prostate cancer[J]. Cell Cycle, 2016, 15(6): 840-849.
[16] Wu GF, Zhang XL, Luo ZG, et al. Metformin therapy and prostate cancer risk: a meta-analysis of observational studies[J]. Int J Clin Exp Med, 2015, 8(8): 13089-13098.
[17] Wedel S, Hudak L, Seibel JM, et al. Inhibitory effects of the HDAC inhibitor valproic acid on prostate cancer growth are enhanced by simultaneous application of the mTOR inhibitor RAD001[J]. Life Sci, 2011, 88(9-10): 418-424.
[18] Tatebe H, Shimizu M, Shirakami Y, et al. Acyclic retinoid synergises with valproic acid to inhibit growth in human hepatocellular carcinoma cells[J]. Cancer Lett, 2009, 285(2): 210-217.
[19] Lan X, Lu G, Yuan C, et al. Valproic acid(VPA)inhibits the epithelial-mesenchymal transition in prostate carcinoma via the dual suppression of SMAD4[J]. J Cancer Res Clin Oncol, 2016, 142(1): 177-185.
[20] Avery LB, Bumpus NN. Valproic acid is a novel activator of AMP-activated protein kinase and decreases liver mass, hepatic fat accumulation, and serum glucose in obese mice[J]. Mol Pharmacol, 2013, 85(1): 1-10.
[21] Juengel E, Dauselt A, Makarevic J, et al. Acetylation of histone H3 prevents resistance development caused by chronic mTOR inhibition in renal cell carcinoma cells[J]. Cancer Lett, 2012, 324(1): 83-90.
[22] Liu JL, Mao Z, Gallick GE, et al. AMPK/TSC2/mTOR-signaling intermediates are not necessary for LKB1-mediated nuclear retention of PTEN tumor suppressor[J]. Neuro Oncol, 2011, 13(2): 184-194.
[1] ZHANG Bingfen, ZHOU Shenghong, WANG Zhe. Trillium Saponins ameliorates pulmonary fibrosis in rats by inhibiting TGF-β/Smad3 and Wnt/β-catenin signaling pathways [J]. Journal of Shandong University (Health Sciences), 2022, 60(8): 23-29.
[2] SUN Haoyu, JIANG Xin, CHEN Shouzhen, QU Sifeng, SHI Benkang. Multiparametric magnetic resonance imaging combined with prostate health index in the diagnosis of prostate cancer in 142 patients within PSA grey zone [J]. Journal of Shandong University (Health Sciences), 2022, 60(6): 46-50.
[3] XU Zhen, DIAO Tongxiang, ZANG Zhenjie, SHAO Dingchang, ZHANG Qi, SUN Dingqi, FU Qiang. Value of isoform［-2］proprostate-specific antigen and its derivatives in the diagnosis of prostate cancer [J]. Journal of Shandong University (Health Sciences), 2022, 60(6): 51-56.
[4] LI Honghao, YU Jing, CHEN Yali, GUO Shougang. Evaluation of CD4+CD25+FoxP3+ regulatory T cells and FoxP3 mRNA expression in 20 NMOSD patients [J]. Journal of Shandong University (Health Sciences), 2022, 60(4): 50-54.
[5] Benkang SHI,Shouzhen CHEN,Sifeng QU,Yong WANG,Lei LIU. Research progress and clinical characteristics of clinical rapidly progressing prostate cancer [J]. Journal of Shandong University (Health Sciences), 2021, 59(9): 110-116.
[6] ZHANG Qian, QIN Mingming, HE Xuejia, CAI Qiujing, ZHANG Yamin, LI Qingsu, ZHU Weiwei. Effects of calcitriol on EMT induced by TGF-β1 in asthma [J]. Journal of Shandong University (Health Sciences), 2021, 59(7): 10-18.
[7] XU Bing, LI Yong, LIU Ming, LIU Yonghui. Silencing PRRX1 gene expression enhances the sensitivity of prostate cancer resistant cell line PC-3/DTX to docetaxel [J]. Journal of Shandong University (Health Sciences), 2021, 59(6): 103-110.
[8] SUN Dingqi, FU Qiang, ZHANG Hui, LIU Shuai, DIAO Tongxiang, CAO Qingwei, ZHANG Keqin. Clinical value of targeted multiparameter MRI and transrectal ultrasonography fusion prostate biopsy for the detection of PI-RADS≥3 prostate cancer [J]. Journal of Shandong University (Health Sciences), 2021, 59(4): 108-113.
[9] HE Pengjuan, YAN Lei, FAN Mingjun, LIU Xiangbin, ZHAO Xingbo. Effects of simvastatin on TGF-β induced epithelial-to-mesenchymal transition in ovarian cancer [J]. Journal of Shandong University (Health Sciences), 2018, 56(5): 46-51.
[10] DONG Wei, XING Naidong, LÜ Jiaju, LIU Shuai, SUN Liang, CAO Qingwei, DONG Yuhao, LIU Zhao, DING Sentai. The therapeutic efficacy of a potent KSP inhibitor S(MeO)TLC against docetaxel-resistant prostate cancer [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2017, 55(9): 23-30.
[11] NIU Jiyuan, WANG Fangli, ZHANG Ruibin, GAO Qingzhen, YUN Ping, WANG Qi, ZHANG Shan, BAI Xue, WANG Xiaoping. Effect of local slow-release coated sirolmus on fistula neointimal hyperplasia [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2016, 54(8): 17-21.
[12] ZHAI Hongyun, ZHANG Denglu, WANG Guangjie, KONG Feng, CHENG Guanghui, ZHAO Shengtian. Effects of factors secreted by mouse embryonic stem cells on prostate cancer cells in vitro [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2015, 53(9): 8-12.
[13] TIAN Yan, HOU Shanrong, LIU Jianli, SUN Xingsheng, HUANG Lihong. Effects of different doses of atorvastatin on the content of TGF-β1 and cardiac structure of dilated cardiomyopathy rats [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2014, 52(9): 6-10.
[14] LAI Cheng-jun1,2, QU Hong-hua3, GUO Xiao-yu4, XING Zhao-quan2, ZHOU Zun-lin2, XU Zhong-hua2, LIU Zhao-xu2,5. The effect of Metformin on the migration and invasion of renal cell carcinoma cells in vitro and its mechanism [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2014, 52(2): 29-32.
[15] DING Huan1, SUN Ying1, LI Xiao-qing2, LI Li1. Effect of PARP inhibitor combined with Gemcitabine or Docetaxel on the  proliferation of androgen-independent prostate cancer cell line PC3 [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2014, 52(1): 33-36.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
No Suggested Reading articles found!
Copyright 2018 © Editorial office of Journal of Shandong University (Health Sciences)
Supported by Beijing Magtech Co.Ltd