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

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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

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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.
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