Abstract
Prostate cancer (PCa) is the most frequent cancer in men. The evolution from local PCa to castration-resistant PCa, an end-stage of disease, is often associated with changes in genes such as p53, androgen receptor, PTEN, and ETS gene fusion products. Evidence is accumulating that repurposing of metformin (MET) and valproic acid (VPA) either when used alone, or in combination, with another therapy, could potentially play a role in slowing down PCa progression. This review provides an overview of the application of MET and VPA, both alone and in combination with other drugs for PCa treatment, correlates the responses to these drugs with common molecular changes in PCa, and then describes the potential for combined MET and VPA as a systemic therapy for prostate cancer, based on potential interacting mechanisms.
Keywords: Metformin, valproic acid, prostate cancer, chemotherapy, mTOR, AMPK, androgen signaling pathway, p53 protein, PTEN, ETS gene fusion, ERG overexpression, histone deacetylase inhibitor.
Graphical Abstract
[2]
Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet‐Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin., 2015, 65(2), 87-108.
[3]
Heidenreich, A.; Bastian, P.J.; Bellmunt, J.; Bolla, M.; Joniau, S.; van der Kwast, T.; Mason, M.; Matveev, V.; Wiegel, T.; Zattoni, F. EAU guidelines on prostate cancer. Part 1: Screening, diagnosis, and local treatment with curative intent-update 2013. Eur. Urol., 2014, 65(1), 124-137.
[4]
Luo, Q.; Yu, X.Q.; Smith, D.P.; O’Connell, D.L. A population-based study of progression to metastatic prostate cancer in Australia. Cancer Epidemiol., 2015, 39(4), 617-622.
[5]
Hirst, C.; Cabrera, C.; Kirby, M. Epidemiology of castration resistant prostate cancer: A longitudinal analysis using a UK primary care database. Cancer Epidemiol., 2012, 36(6), e349-e353.
[6]
Ryan, C.J.; Smith, M.R.; Fizazi, K.; Saad, F.; Mulders, P.F.; Sternberg, C.N.; Miller, K.; Logothetis, C.J.; Shore, N.D.; Small, E.J. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): Final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol., 2015, 16(2), 152-160.
[7]
Beer, T.M.; Armstrong, A.J.; Rathkopf, D.E.; Loriot, Y.; Sternberg, C.N.; Higano, C.S.; Iversen, P.; Bhattacharya, S.; Carles, J.; Chowdhury, S. Enzalutamide in metastatic prostate cancer before chemotherapy. N. Engl. J. Med., 2014, 371(5), 424-433.
[8]
Tannock, I.F.; de Wit, R.; Berry, W.R.; Horti, J.; Pluzanska, A.; Chi, K.N.; Oudard, S.; Théodore, C.; James, N.D.; Turesson, I. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N. Engl. J. Med., 2004, 351(15), 1502-1512.
[9]
Kantoff, P.W.; Higano, C.S.; Shore, N.D.; Berger, E.R.; Small, E.J.; Penson, D.F.; Redfern, C.H.; Ferrari, A.C.; Dreicer, R.; Sims, R.B. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med., 2010, 363(5), 411-422.
[10]
De Bono, J.S.; Oudard, S.; Ozguroglu, M.; Hansen, S.; Machiels, J-P.; Kocak, I.; Gravis, G.; Bodrogi, I.; Mackenzie, M.J.; Shen, L. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet, 2010, 376(9747), 1147-1154.
[11]
Nilsson, S.; Franzén, L.; Parker, C.; Tyrrell, C.; Blom, R.; Tennvall, J.; Lennernäs, B.; Petersson, U.; Johannessen, D.C.; Sokal, M. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: A randomised, multicentre, placebo-controlled phase II study. Lancet Oncol., 2007, 8(7), 587-594.
[12]
Müller, H.; Reinwein, H. Zur Pharmakologie des Galegins. Naunyn-Schmiedebergs Archiv experiment. Pathol. Pharmakol, 1927, 125(3-4), 212-228.
[13]
Shaw, R.J.; Lamia, K.A.; Vasquez, D.; Koo, S-H.; Bardeesy, N.; DePinho, R.A.; Montminy, M.; Cantley, L.C. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science, 2005, 310(5754), 1642-1646.
[14]
Kozka, I.; Clark, A.; Reckless, J.; Cushman, S.; Gould, G.; Holman, G. The effects of insulin on the level and activity of the GLUT4 present in human adipose cells. Diabetologia, 1995, 38(6), 661-666.
[15]
Burton, B. On the propyl derivatives and decomposition products of ethylacetoacetate. J. Am. Chem. Soc., 1882, 3, 385-395.
[16]
Meunier, H.; Carraz, G.; Neunier, Y.; Eymard, P.; Aimard, M. Pharmacodynamic properties of N-dipropylacetic acid. Therapie, 1962, 18, 435-438.
[17]
Chen, Y.; Pan, R.L.; Zhang, X.L.; Shao, J.Z.; Xiang, L.X.; Dong, X.J.; Zhang, G.R. Induction of hepatic differentiation of mouse bone marrow stromal stem cells by the histone deacetylase inhibitor VPA. J. Cell. Mol. Med., 2009, 13(8b), 2582-2592.
[18]
Zhou, G.; Myers, R.; Li, Y.; Chen, Y.; Shen, X.; Fenyk-Melody, J.; Wu, M.; Ventre, J.; Doebber, T.; Fujii, N. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest., 2001, 108(8), 1167-1174.
[19]
Ben-Sahra, I.; Laurent, K.; Loubat, A.; Giorgetti-Peraldi, S.; Colosetti, P.; Auberger, P.; Tanti, J-F.; Le Marchand-Brustel, Y.; Bost, F. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene, 2008, 27(25), 3576-3586.
[20]
Bolster, D.R.; Crozier, S.J.; Kimball, S.R.; Jefferson, L.S. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. J. Biol. Chem., 2002, 277(27), 23977-23980.
[21]
Long, Y.C.; Zierath, J.R. AMP-activated protein kinase signaling in metabolic regulation. J. Clin. Invest., 2006, 116(7), 1776-1783.
[22]
Bradbury, C.; Khanim, F.; Hayden, R.; Bunce, C.; White, D.; Drayson, M.; Craddock, C.; Turner, B. Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia, 2005, 19(10), 1751-1759.
[23]
Rosato, R.R.; Almenara, J.A.; Grant, S. The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1. Cancer Res., 2003, 63(13), 3637-3645.
[24]
Savickiene, J.; Borutinskaite, V-V.; Treigyte, G.; Magnusson, K-E.; Navakauskiene, R. The novel histone deacetylase inhibitor BML-210 exerts growth inhibitory, proapoptotic and differentiation stimulating effects on the human leukemia cell lines. Eur. J. Pharmacol., 2006, 549(1), 9-18.
[25]
Martirosyan, A.; Leonard, S.; Shi, X.; Griffith, B.; Gannett, P.; Strobl, J. Actions of a histone deacetylase inhibitor NSC3852 (5-nitroso-8-quinolinol) link reactive oxygen species to cell differentiation and apoptosis in MCF-7 human mammary tumor cells. J. Pharmacol. Exp. Ther., 2006, 317(2), 546-552.
[26]
Rothermundt, C.; Hayoz, S.; Templeton, A.J.; Winterhalder, R.; Strebel, R.T.; Bärtschi, D.; Pollak, M.; Lui, L.; Endt, K.; Schiess, R. Metformin in chemotherapy-naive castration-resistant prostate cancer: a multicenter phase 2 trial (SAKK 08/09). Eur. Urol., 2014, 66(3), 468-474.
[27]
Azoulay, L.; Dell’Aniello, S.; Gagnon, B.; Pollak, M.; Suissa, S. Metformin and the incidence of prostate cancer in patients with type 2 diabetes. Cancer Epidemiol. Biomarkers Prev., 2011, 20(2), 337-344.
[28]
Joerger, M.; van Schaik, R.; Becker, M.; Hayoz, S.; Pollak, M.; Cathomas, R.; Winterhalder, R.; Gillessen, S.; Rothermundt, C. Multidrug and toxin extrusion 1 and human organic cation transporter 1 polymorphisms in patients with castration-resistant prostate cancer receiving metformin (SAKK 08/09). Prostate Cancer Prostatic Dis., 2015, 18(2), 167-172.
[29]
Fendt, S-M.; Bell, E.L.; Keibler, M.A.; Davidson, S.M.; Wirth, G.J.; Fiske, B.; Mayers, J.R.; Schwab, M.; Bellinger, G.; Csibi, A. Metformin decreases glucose oxidation and increases the dependency of prostate cancer cells on reductive glutamine metabolism. Cancer Res., 2013, 73(14), 4429-4438.
[30]
Ben-Sahra, I.; Regazzetti, C.; Robert, G.; Laurent, K.; Le Marchand-Brustel, Y.; Auberger, P.; Tanti, J-F.; Giorgetti-Peraldi, S.; Bost, F. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res., 2011, 71(13), 4366-4372.
[31]
Vecchio, S.; Giampreti, A.; Petrolini, V.; Lonati, D.; Protti, A.; Papa, P.; Rognoni, C.; Valli, A.; Rocchi, L.; Rolandi, L. Metformin accumulation: Lactic acidosis and high plasmatic metformin levels in a retrospective case series of 66 patients on chronic therapy. Clin. Toxicol., 2014, 52(2), 129-135.
[32]
Dowling, R.J.; Niraula, S.; Stambolic, V.; Goodwin, P.J. Metformin in cancer: translational challenges. J. Mol. Endocrinol., 2012, 48(3), R31-R43.
[33]
Carducci, M.A.; Gilbert, J.; Bowling, M.K.; Noe, D.; Eisenberger, M.A.; Sinibaldi, V.; Zabelina, Y.; Chen, T-I.; Grochow, L.B.; Donehower, R.C. A Phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-h infusion schedule. Clin. Cancer Res., 2001, 7(10), 3047-3055.
[34]
Sandor, V.; Bakke, S.; Robey, R.W.; Kang, M.H.; Blagosklonny, M.V.; Bender, J.; Brooks, R.; Piekarz, R.L.; Tucker, E.; Figg, W.D. Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms. Clin. Cancer Res., 2002, 8(3), 718-728.
[35]
Kelly, W.K.; O’connor, O.A.; Krug, L.M.; Chiao, J.H.; Heaney, M.; Curley, T.; MacGregore-Cortelli, B.; Tong, W.; Secrist, J.P.; Schwartz, L. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J. Clin. Oncol., 2005, 23(17), 3923-3931.
[36]
Shabbeer, S.; Kortenhorst, M.S.Q.; Kachhap, S.; Galloway, N.; Rodriguez, R.; Carducci, M.A. Multiple molecular pathways explain the anti‐proliferative effect of valproic acid on prostate cancer cells in vitro and in vivo. Prostate, 2007, 67(10), 1099-1110.
[37]
Sidana, A.; Wang, M.; Shabbeer, S.; Chowdhury, W.H.; Netto, G.; Lupold, S.E.; Carducci, M.; Rodriguez, R. Mechanism of growth inhibition of prostate cancer xenografts by valproic acid. J. Biomed. Biotechnol., 2012, 2012, 180363.
[38]
Yang, H.; Hoshino, K.; Sanchez-Gonzalez, B.; Kantarjian, H.; Garcia-Manero, G. Antileukemia activity of the combination of 5-aza-2′-deoxycytidine with valproic acid. Leuk. Res., 2005, 29(7), 739-748.
[39]
Atmaca, A.; Al-Batran, S.E.; Maurer, A.; Neumann, A.; Heinzel, T.; Hentsch, B.; Schwarz, S.E.; Hovelmann, S.; Gottlicher, M.; Knuth, A.; Jager, E. Valproic acid (VPA) in patients with refractory advanced cancer: a dose escalating phase I clinical trial. Br. J. Cancer, 2007, 97(2), 177-182.
[40]
Friedmann, I.; Atmaca, A.; Chow, K.U.; Jager, E.; Weidmann, E. Synergistic effects of valproic acid and mitomycin C in adenocarcinoma cell lines and fresh tumor cells of patients with colon cancer. J. Chemother., 2006, 18(4), 415-420.
[41]
Sharma, S.; Symanowski, J.; Wong, B.; Dino, P.; Manno, P.; Vogelzang, N. A phase II clinical trial of oral valproic acid in patients with castration-resistant prostate cancers using an intensive biomarker sampling strategy. Transl. Oncol., 2008, 1(3), 141.
[42]
Mahalingam, D.; Medina, E.C.; Esquivel, J.A.; Espitia, C.M.; Smith, S.; Oberheu, K.; Swords, R.; Kelly, K.R.; Mita, M.M.; Mita, A.C. Vorinostat enhances the activity of temsirolimus in renal cell carcinoma through suppression of survivin levels. Clin. Cancer Res., 2010, 16(1), 141-153.
[43]
Vogelstein, B.; Papadopoulos, N.; Velculescu, V.E.; Zhou, S.; Diaz, L.A.; Kinzler, K.W. Cancer genome landscapes. Science, 2013, 339(6127), 1546-1558.
[44]
Gerlinger, M.; Rowan, A.J.; Horswell, S.; Larkin, J.; Endesfelder, D.; Gronroos, E.; Martinez, P.; Matthews, N.; Stewart, A.; Tarpey, P. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med., 2012, 2012(366), 883-892.
[45]
Dienstmann, R.; Jang, I.S.; Bot, B.; Friend, S.; Guinney, J. Database of genomic biomarkers for cancer drugs and clinical targetability in solid tumors. Cancer Discov., 2015, 5(2), 118-123.
[46]
So, A.; Gleave, M.; Hurtado-Col, A.; Nelson, C. Mechanisms of the development of androgen independence in prostate cancer. World J. Urol., 2005, 23(1), 1-9.
[47]
Gravis, G.; Fizazi, K.; Joly, F.; Oudard, S.; Priou, F.; Esterni, B.; Latorzeff, I.; Delva, R.; Krakowski, I.; Laguerre, B. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): A randomised, open-label, phase 3 trial. Lancet Oncol., 2013, 14(2), 149-158.
[48]
James, N.D.; Sydes, M.R.; Clarke, N.W.; Mason, M.D.; Dearnaley, D.P.; Spears, M.R.; Ritchie, A.W.; Parker, C.C.; Russell, J.M.; Attard, G. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet, 2016, 387(10024), 1163-1177.
[49]
Colquhoun, A.; Venier, N.; Vandersluis, A.; Besla, R.; Sugar, L.; Kiss, A.; Fleshner, N.; Pollak, M.; Klotz, L.; Venkateswaran, V. Metformin enhances the antiproliferative and apoptotic effect of bicalutamide in prostate cancer. Prostate Cancer Prostatic Dis., 2012, 15(4), 346-352.
[50]
Wang, Y.; Liu, G.; Tong, D.; Parmar, H.; Hasenmayer, D.; Yuan, W.; Zhang, D.; Jiang, J. Metformin represses androgen-dependent and androgen-independent prostate cancers by targeting androgen receptor. Prostate, 2015, 75(11), 1187-1196.
[51]
Chen-Pin, W.; Javier, H.; Lorenzo, C.; Downs, J.R.; Thompson, I.M.; Pollock, B.; Lehman, D. Statins and finasteride use differentially modify the impact of metformin on prostate cancer incidence in men with type 2 diabetes. Ann. Transl. Med. Epidemiol., 2014, 1(1), 1004.
[53]
Ben-Sahra, I.; Laurent, K.; Giuliano, S.; Larbret, F.; Ponzio, G.; Gounon, P.; Le Marchand-Brustel, Y.; Giorgetti-Peraldi, S.; Cormont, M.; Bertolotto, C. Targeting cancer cell metabolism: The combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res., 2010, 70(6), 2465-2475.
[54]
Lehman, D.M.; Lorenzo, C.; Hernandez, J.; Wang, C.P. Statin use as a moderator of metformin effect on risk for prostate cancer among type 2 diabetic patients. Diabetes Care, 2012, 35(5), 1002-1007.
[55]
Danzig, M.R.; Kotamarti, S.; Ghandour, R.A.; Rothberg, M.B.; Dubow, B.P.; Benson, M.C.; Badani, K.K.; McKiernan, J.M. Synergism between metformin and statins in modifying the risk of biochemical recurrence following radical prostatectomy in men with diabetes. Prostate Cancer Prostatic Dis., 2015, 18(1), 63-68.
[56]
Babcook, M.A.; Shukla, S.; Fu, P.; Vazquez, E.J.; Puchowicz, M.A.; Molter, J.P.; Oak, C.Z.; MacLennan, G.T.; Flask, C.A.; Lindner, D.J. Synergistic simvastatin and metformin combination chemotherapy for osseous metastatic castration-resistant prostate cancer. Mol. Cancer Ther., 2014, 13(10), 2288-2302.
[57]
Pennanen, P.; Syvala, H.; Blauer, M.; Savinainen, K.; Ylikomi, T.; Tammela, T.L.; Murtola, T.J. The effects of metformin and simvastatin on the growth of LNCaP and RWPE-1 prostate epithelial cell lines. Eur. J. Pharmacol., 2016, 788, 160-167.
[58]
Saha, A.; Blando, J.; Tremmel, L.; DiGiovanni, J. Effect of metformin, rapamycin, and their combination on growth and progression of prostate tumors in HiMyc mice. Cancer Prev. Res., 2015, 8(7), 597-606.
[59]
Al-Hendy, A.; Diamond, M.P.; Boyer, T.G.; Halder, S.K. Vitamin D3 inhibits Wnt/β-catenin and mTOR signaling pathways in human uterine fibroid cells. J. Clin. Endocrinol. Metab., 2016, 101(4), 1542-1551.
[60]
Li, H.X.; Gao, J.M.; Liang, J.Q.; Xi, J.M.; Fu, M.; Wu, Y.J. Vitamin D3 potentiates the growth inhibitory effects of metformin in DU145 human prostate cancer cells mediated by AMPK/mTOR signalling pathway. Clin. Exp. Pharmacol. Physiol., 2015, 42(6), 711-717.
[61]
Cinatl, J., Jr; Cinatl, J.; Scholz, M.; Driever, P.H.; Henrich, D.; Kabickova, H.; Vogel, J-U.; Doerr, H.W.; Kornhuber, B. Antitumor activity of sodium valproate in cultures of human neuroblastoma cells. Anticancer Drugs, 1996, 7(7), 766-773.
[62]
Ouyang, D-Y.; Ji, Y-H.; Saltis, M.; Xu, L-H.; Zhang, Y-T.; Zha, Q-B.; Cai, J-Y.; He, X-H. Valproic acid synergistically enhances the cytotoxicity of gossypol in DU145 prostate cancer cells: An iTRTAQ-based quantitative proteomic analysis. J. Proteomics, 2011, 74(10), 2180-2193.
[63]
Wissing, M.D.; Mendonca, J.; Kortenhorst, M.S.; Kaelber, N.S.; Gonzalez, M.; Kim, E.; Hammers, H.; van Diest, P.J.; Carducci, M.A.; Kachhap, S.K. Targeting prostate cancer cell lines with polo-like kinase 1 inhibitors as a single agent and in combination with histone deacetylase inhibitors. FASEB J., 2013, 27(10), 4279-4293.
[64]
Paller, C.J.; Wissing, M.D.; Mendonca, J.; Sharma, A.; Kim, E.; Kim, H.S.; Kortenhorst, M.S.; Gerber, S.; Rosen, M.; Shaikh, F.; Zahurak, M.L.; Rudek, M.A.; Hammers, H.; Rudin, C.M.; Carducci, M.A.; Kachhap, S.K. Combining the pan-aurora kinase inhibitor AMG 900 with histone deacetylase inhibitors enhances antitumor activity in prostate cancer. Cancer Med., 2014, 3(5), 1322-1335.
[65]
Qian, D.Z.; Wang, X.; Kachhap, S.K.; Kato, Y.; Wei, Y.; Zhang, L.; Atadja, P.; Pili, R. The histone deacetylase inhibitor NVP-LAQ824 inhibits angiogenesis and has a greater antitumor effect in combination with the vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584. Cancer Res., 2004, 64(18), 6626-6634.
[66]
Wheler, J.J.; Janku, F.; Falchook, G.S.; Jackson, T.L.; Fu, S.; Naing, A.; Tsimberidou, A.M.; Moulder, S.L.; Hong, D.S.; Yang, H.; Piha-Paul, S.A.; Atkins, J.T.; Garcia-Manero, G.; Kurzrock, R. Phase I study of anti-VEGF monoclonal antibody bevacizumab and histone deacetylase inhibitor valproic acid in patients with advanced cancers. Cancer Chemother. Pharmacol., 2014, 73(3), 495-501.
[67]
Wedel, S.; Hudak, L.; Seibel, J.M.; Juengel, E.; Oppermann, E.; Haferkamp, A.; Blaheta, R.A. Critical analysis of simultaneous blockage of histone deacetylase and multiple receptor tyrosine kinase in the treatment of prostate cancer. The Prostate, 2011, 71(7), 722-735.
[68]
Annicotte, J.S.; Iankova, I.; Miard, S.; Fritz, V.; Sarruf, D.; Abella, A.; Berthe, M.L.; Noel, D.; Pillon, A.; Iborra, F.; Dubus, P.; Maudelonde, T.; Culine, S.; Fajas, L. Peroxisome proliferator-activated receptor gamma regulates E-cadherin expression and inhibits growth and invasion of prostate cancer. Mol. Cell. Biol., 2006, 26(20), 7561-7574.
[69]
Fortson, W.S.; Kayarthodi, S.; Fujimura, Y.; Xu, H.; Matthews, R.; Grizzle, W.E.; Rao, V.N.; Bhat, G.K.; Reddy, E.S.P. Histone deacetylase inhibitors, valproic acid and trichostatin-A induce apoptosis and affect acetylation status of p53 in ERG-positive prostate cancer cells. Int. J. Oncol., 2011, 39(1), 111.
[70]
David, K.A.; Mongan, N.P.; Smith, C.; Gudas, L.J.; Nanus, D.M. Phase I trial of ATRA-IV and depakote in patients with advanced solid tumor malignancies. Cancer Biol. Ther., 2010, 9(9), 678-684.
[71]
Wedel, S.; Hudak, L.; Seibel, J.M.; Juengel, E.; Tsaur, I.; Wiesner, C.; Haferkamp, A.; Blaheta, R.A. Inhibitory effects of the HDAC inhibitor valproic acid on prostate cancer growth are enhanced by simultaneous application of the mTOR inhibitor RAD001. Life sciences, 2011, 88(9-10), 418-424.
[72]
Zhang, X.; Zhang, X.; Huang, T.; Geng, J.; Liu, M.; Zheng, J. Combination of metformin and valproic acid synergistically induces cell cycle arrest and apoptosis in clear cell renal cell carcinoma. Int. J. Clin. Exp. Pathol., 2015, 8(3), 2823-2828.
[73]
Tran, L.N.; Kichenadasse, G.; Butler, L.M.; Centenera, M.M.; Morel, K.L.; Ormsby, R.J.; Michael, M.Z.; Lower, K.M.; Sykes, P.J. The combination of metformin and valproic acid induces synergistic apoptosis in the presence of p53 and androgen signaling in prostate cancer. Mol. Cancer Ther., 2017, 16(12), 2689-2700.
[74]
Robinson, D.; Van Allen, E.M.; Wu, Y-M.; Schultz, N.; Lonigro, R.J.; Mosquera, J-M.; Montgomery, B.; Taplin, M-E.; Pritchard, C.C.; Attard, G. Integrative clinical genomics of advanced prostate cancer. Cell, 2015, 161(5), 1215-1228.
[75]
Taplin, M-E.; Bubley, G.J.; Shuster, T.D.; Frantz, M.E.; Spooner, A.E.; Ogata, G.K.; Keer, H.N.; Balk, S.P. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N. Engl. J. Med., 1995, 332(21), 1393-1398.
[76]
Feldman, B.J.; Feldman, D. The development of androgen-independent prostate cancer. Nat. Rev. Cancer, 2001, 1(1), 34-45.
[77]
Bookstein, R.; MacGrogan, D.; Hilsenbeck, S.G.; Sharkey, F.; Allred, D.C. p53 is mutated in a subset of advanced-stage prostate cancers. Cancer Res., 1993, 53(14), 3369-3373.
[78]
Zakikhani, M.; Dowling, R.; Fantus, I.G.; Sonenberg, N.; Pollak, M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res., 2006, 66(21), 10269-10273.
[79]
Gotlieb, W.H.; Saumet, J.; Beauchamp, M-C.; Gu, J.; Lau, S.; Pollak, M.N.; Bruchim, I. In vitro metformin anti-neoplastic activity in epithelial ovarian cancer. Gynecol. Oncol., 2008, 110(2), 246-250.
[80]
Okoshi, R.; Ozaki, T.; Yamamoto, H.; Ando, K.; Koida, N.; Ono, S.; Koda, T.; Kamijo, T.; Nakagawara, A.; Kizaki, H. Activation of AMP-activated protein kinase induces p53-dependent apoptotic cell death in response to energetic stress. J. Biol. Chem., 2008, 283(7), 3979-3987.
[81]
Feng, Z.; Levine, A.J. The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein. Trends Cell Biol., 2010, 20(7), 427-434.
[82]
Bensaad, K.; Vousden, K.H. p53: New roles in metabolism. Trends Cell Biol., 2007, 17(6), 286-291.
[83]
Chen, L.; Ahmad, N.; Liu, X. Combining p53 stabilizers with metformin induces synergistic apoptosis through regulation of energy metabolism in castration-resistant prostate cancer. Cell Cycle, 2016, 15(6), 840-849.
[84]
Bode, A.M.; Dong, Z. Post-translational modification of p53 in tumorigenesis. Nat. Rev. Cancer, 2004, 4(10), 793-805.
[85]
Gu, W.; Roeder, R.G. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell, 1997, 90(4), 595-606.
[86]
Feng, Z.; Hu, W.; De Stanchina, E.; Teresky, A.K.; Jin, S.; Lowe, S.; Levine, A.J. The regulation of AMPK β1, TSC2, and PTEN expression by p53: Stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res., 2007, 67(7), 3043-3053.
[87]
Hardie, D.G. Minireview: The AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology, 2003, 144(12), 5179-5183.
[88]
Nicolini, C.; Ahn, Y.; Michalski, B.; Rho, J.M.; Fahnestock, M. Decreased mTOR signaling pathway in human idiopathic autism and in rats exposed to valproic acid. Acta Neuropathol. Commun., 2015, 3(1), 3.
[89]
Wedel, S.; Hudak, L.; Seibel, J.M.; Makarevic, J.; Juengel, E.; Tsaur, I.; Wiesner, C.; Haferkamp, A.; Blaheta, R.A. Impact of combined HDAC and mTOR inhibition on adhesion, migration and invasion of prostate cancer cells. Clin. Exp. Metastasis, 2011, 28(5), 479-491.
[90]
Chen, H.; Dzitoyeva, S.; Manev, H. Effect of valproic acid on mitochondrial epigenetics. Eur. J. Pharmacol., 2012, 690(1), 51-59.
[91]
Li, Y.; Chan, S.C.; Brand, L.J.; Hwang, T.H.; Silverstein, K.A.; Dehm, S.M. Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res., 2013, 73(2), 483-489.
[92]
Tran, C.; Ouk, S.; Clegg, N.J.; Chen, Y.; Watson, P.A.; Arora, V.; Wongvipat, J.; Smith-Jones, P.M.; Yoo, D.; Kwon, A. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science, 2009, 324(5928), 787-790.
[93]
Xu, Y.; Chen, S-Y.; Ross, K.N.; Balk, S.P. Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin activation and post-transcriptional increases in cyclin D proteins. Cancer Res., 2006, 66(15), 7783-7792.
[94]
Gaughan, L.; Logan, I.R.; Cook, S.; Neal, D.E.; Robson, C.N. Tip60 and histone deacetylase 1 regulate androgen receptor activity through changes to the acetylation status of the receptor. J. Biol. Chem., 2002, 277(29), 25904-25913.
[95]
Xia, Q.; Sung, J.; Chowdhury, W.; Chen, C-I.; Höti, N.; Shabbeer, S.; Carducci, M.; Rodriguez, R. Chronic administration of valproic acid inhibits prostate cancer cell growth in vitro and in vivo. Cancer Res., 2006, 66(14), 7237-7244.
[96]
Iacopino, F.; Urbano, R.; Graziani, G.; Muzi, A.; Navarra, P.; Sica, G. Valproic acid activity in androgen-sensitive and-insensitive human prostate cancer cells. Int. J. Oncol., 2008, 32(6), 1293-1303.
[97]
Chou, Y-W.; Chaturvedi, N.K.; Ouyang, S.; Lin, F-F.; Kaushik, D.; Wang, J.; Kim, I.; Lin, M-F. Histone deacetylase inhibitor valproic acid suppresses the growth and increases the androgen responsiveness of prostate cancer cells. Cancer Lett., 2011, 311(2), 177-186.
[98]
Sobel, R.E.; Wang, Y.; Sadar, M.D. Molecular analysis and characterization of PrEC, commercially available prostate epithelial cells. In Vitro Cell. Dev. Biol. Anim., 2006, 42(1-2), 33-39.
[99]
Kumari, S.; Schlanger, S.; Wang, D.; Liu, S.; Heemers, H. OR43-2:
defining co-regulator contribution to AR-dependent transcription
uncovers a novel AR-WDR77-p53-dependent transcriptional code. In Endocrine Society's 98th Annual Meeting and Expo, Endocrine
Society: Boston, 2016.
[100]
Tomlins, S.A.; Rhodes, D.R.; Perner, S.; Dhanasekaran, S.M.; Mehra, R.; Sun, X-W.; Varambally, S.; Cao, X.; Tchinda, J.; Kuefer, R.; Lee, C.; Montie, J.E.; Shah, R.B.; Pienta, K.J.; Rubin, M.A.; Chinnaiyan, A.M. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science, 2005, 310(5748), 644-648.
[101]
Li, J.; Yen, C.; Liaw, D.; Podsypanina, K.; Bose, S.; Wang, S.I.; Puc, J.; Miliaresis, C.; Rodgers, L.; McCombie, R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science, 1997, 275(5308), 1943-1947.
[102]
Attard, G.; Swennenhuis, J.F.; Olmos, D.; Reid, A.H.; Vickers, E.; A’Hern, R.; Levink, R.; Coumans, F.; Moreira, J.; Riisnaes, R. Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res., 2009, 69(7), 2912-2918.
[103]
Bastola, D.R.; Pahwa, G.S.; Lin, M-F.; Cheng, P-W. Downregulation of PTEN/MMAC/TEP1 expression in human prostate cancer cell line DU145 by growth stimuli. Mol. Cell. Biochem., 2002, 236(1), 75-81.
[104]
Vazquez, F.; Ramaswamy, S.; Nakamura, N.; Sellers, W.R. Phosphorylation of the PTEN tail regulates protein stability and function. Mol. Cell. Biol., 2000, 20(14), 5010-5018.
[105]
Hara, S.; Oya, M.; Mizuno, R.; Horiguchi, A.; Marumo, K.; Murai, M. Akt activation in renal cell carcinoma: contribution of a decreased PTEN expression and the induction of apoptosis by an Akt inhibitor. Ann. Oncol., 2005, 16(6), 928-933.
[106]
John, J.S.; Powell, K.; Conley-LaComb, M.K.; Chinni, S.R. TMPRSS2-ERG fusion gene expression in prostate tumor cells and its clinical and biological significance in prostate cancer progression. J. Cancer Sci. Ther., 2012, 4(4), 94.
[107]
Rubin, M.A.; Maher, C.A.; Chinnaiyan, A.M. Common gene rearrangements in prostate cancer. J. Clin. Oncol., 2011, 29(27), 3659-3668.
[108]
Friedlander, T.W.; Roy, R.; Tomlins, S.A.; Ngo, V.T.; Kobayashi, Y.; Azameera, A.; Rubin, M.A.; Pienta, K.J.; Chinnaiyan, A.; Ittmann, M.M. Common structural and epigenetic changes in the genome of castration-resistant prostate cancer. Cancer Res., 2012, 72(3), 616-625.
[110]
Rahim, S.; Üren, A. Emergence of ETS transcription factors as diagnostic tools and therapeutic targets in prostate cancer. Am. J. Transl. Res., 2013, 5(3), 254.
[111]
Tomlins, S.A.; Laxman, B.; Varambally, S.; Cao, X.; Yu, J.; Helgeson, B.E.; Cao, Q.; Prensner, J.R.; Rubin, M.A.; Shah, R.B. Role of the TMPRSS2-ERG gene fusion in prostate cancer. Neoplasia (New York, NY), 2008, 10(2), 177.
[112]
Massoner, P.; Kugler, K.G.; Unterberger, K.; Kuner, R.; Mueller, L.A.; Fälth, M.; Schäfer, G.; Seifarth, C.; Ecker, S.; Verdorfer, I. Characterization of transcriptional changes in ERG rearrangement-positive prostate cancer identifies the regulation of metabolic sensors such as neuropeptide Y. PLoS One, 2013, 8(2), e55207.
[113]
Björkman, M.; Iljin, K.; Halonen, P.; Sara, H.; Kaivanto, E.; Nees, M.; Kallioniemi, O.P. Defining the molecular action of HDAC inhibitors and synergism with androgen deprivation in ERG‐positive prostate cancer. Int. J. Cancer, 2008, 123(12), 2774-2781.
[114]
Carver, B.S.; Tran, J.; Gopalan, A.; Chen, Z.; Shaikh, S.; Carracedo, A.; Alimonti, A.; Nardella, C.; Varmeh, S.; Scardino, P.T. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat. Genet., 2009, 41(5), 619-624.
[115]
Reid, A.; Attard, G.; Ambroisine, L.; Fisher, G.; Kovacs, G.; Brewer, D.; Clark, J.; Flohr, P.; Edwards, S.; Berney, D. Molecular characterisation of ERG, ETV1 and PTEN gene loci identifies patients at low and high risk of death from prostate cancer. Br. J. Cancer, 2010, 102(4), 678-684.
[116]
Bergheim, I.; Guo, L.; Davis, M.A.; Lambert, J.C.; Beier, J.I.; Duveau, I.; Luyendyk, J.P.; Roth, R.A.; Arteel, G.E. Metformin prevents alcohol-induced liver injury in the mouse: Critical role of plasminogen activator inhibitor-1. Gastroenterology, 2006, 130(7), 2099-2112.
[117]
Van Beneden, K.; Geers, C.; Pauwels, M.; Mannaerts, I.; Verbeelen, D.; van Grunsven, L.A.; Van den Branden, C. Valproic acid attenuates proteinuria and kidney injury. J. Am. Soc. Nephrol., 2011, 22(10), 1863-1875.
[118]
El Sheikh, S.S.; Romanska, H.M.; Abel, P.; Domin, J.; Lalani, E-N. Predictive value of PTEN and AR coexpression of sustained responsiveness to hormonal therapy in prostate cancer-a pilot study. Neoplasia, 2008, 10(9), 949-953.
[119]
Taylor, B.S.; Schultz, N.; Hieronymus, H.; Gopalan, A.; Xiao, Y.; Carver, B.S.; Arora, V.K.; Kaushik, P.; Cerami, E.; Reva, B. Integrative genomic profiling of human prostate cancer. Cancer Cell, 2010, 18(1), 11-22.
[120]
Wu, X.; Senechal, K.; Neshat, M.S.; Whang, Y.E.; Sawyers, C.L. The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc. Natl. Acad. Sci., 1998, 95(26), 15587-15591.
[121]
Marcelli, M.; Ittmann, M.; Mariani, S.; Sutherland, R.; Nigam, R.; Murthy, L.; Zhao, Y.; DiConcini, D.; Puxeddu, E.; Esen, A. Androgen receptor mutations in prostate cancer. Cancer Res., 2000, 60(4), 944-949.
[122]
Currie, C.; Poole, C.; Gale, E. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia, 2009, 52(9), 1766-1777.
[123]
Nobes, J.P.; Langley, S.E.; Klopper, T.; Russell-Jones, D.; Laing, R.W. A prospective, randomized pilot study evaluating the effects of metformin and lifestyle intervention on patients with prostate cancer receiving androgen deprivation therapy. BJU Int., 2012, 109(10), 1495-1502.
[124]
Monteagudo, S.; Perez-Martinez, F.C.; Perez-Carrion, M.D.; Guerra, J.; Merino, S.; Sanchez-Verdu, M.P.; Cena, V. Inhibition of p42 MAPK using a nonviral vector-delivered siRNA potentiates the anti-tumor effect of metformin in prostate cancer cells. Nanomedicine, 2012, 7(4), 493-506.
[125]
Babcook, M.A.; Sramkoski, R.M.; Fujioka, H.; Daneshgari, F.; Almasan, A.; Shukla, S.; Nanavaty, R.R.; Gupta, S. Combination simvastatin and metformin induces G1-phase cell cycle arrest and Ripk1- and Ripk3-dependent necrosis in C4-2B osseous metastatic castration-resistant prostate cancer cells. Cell Death Dis., 2014, 5, e1536.
[126]
Bilen, M.A.; Lin, S.H.; Tang, D.G.; Parikh, K.; Lee, M.H.; Yeung, S.C.; Tu, S.M. Maintenance therapy containing metformin and/or zyflamend for advanced prostate cancer: A case series. Case Rep. Oncol. Med., 2015, 2015, 471861.
[127]
White-Al Habeeb, N.M.; Garcia, J.; Fleshner, N.; Bapat, B. Metformin elicits antitumor effects and downregulates the histone methyltransferase multiple myeloma SET domain (MMSET) in prostate cancer cells. Prostate, 2016, 76(16), 1507-1518.
[128]
Gonnissen, A.; Isebaert, S.; McKee, C.M.; Muschel, R.J.; Haustermans, K. The effect of metformin and GANT61 combinations on the radiosensitivity of prostate cancer cells. Int. J. Mol. Sci., 2017, 18(2), 399.
[129]
Mayer, M.J.; Klotz, L.H.; Venkateswaran, V. The Effect of metformin use during docetaxel chemotherapy on prostate cancer specific and overall survival of diabetic patients with castration resistant prostate cancer. J. Urol., 2017, 197(4), 1068-1075.
[130]
Gavrilov, V.; Leibovich, Y.; Ariad, S.; Lavrenkov, K.; Shany, S. A combined pretreatment of 1,25-dihydroxyvitamin D3 and sodium valproate enhances the damaging effect of ionizing radiation on prostate cancer cells. J. Steroid Biochem. Mol. Biol., 2010, 121(1-2), 391-394.
[131]
Wedel, S.; Hudak, L.; Seibel, J.M.; Makarevic, J.; Juengel, E.; Tsaur, I.; Waaga-Gasser, A.; Haferkamp, A.; Blaheta, R.A. Molecular targeting of prostate cancer cells by a triple drug combination down-regulates integrin driven adhesion processes, delays cell cycle progression and interferes with the CDK-cyclin axis. BMC Cancer, 2011, 11, 375.
[132]
Hudak, L.; Tezeeh, P.; Wedel, S.; Makarevic, J.; Juengel, E.; Tsaur, I.; Bartsch, G.; Wiesner, C.; Haferkamp, A.; Blaheta, R.A. Low dosed interferon alpha augments the anti-tumor potential of histone deacetylase inhibition on prostate cancer cell growth and invasion. Prostate, 2012, 72(16), 1719-1735.
[133]
Abrahamsson, P-A. Improving outcomes in prostate cancer: Time to tackle bone disorders. Eur. Urol. Suppl., 2009, 8(11), 821-822.
[134]
Xie, Z.; Dong, Y.; Scholz, R.; Neumann, D.; Zou, M-H. Phosphorylation of LKB1 at serine 428 by protein kinase C-ζ is required for metformin-enhanced activation of the AMP-activated protein kinase in endothelial cells. Circulation, 2008, 117(7), 952-962.
[135]
Wheaton, W.W.; Weinberg, S.E.; Hamanaka, R.B.; Soberanes, S.; Sullivan, L.B.; Anso, E.; Glasauer, A.; Dufour, E.; Mutlu, G.M.; Budigner, G.S. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife, 2014, 3, e02242.
[136]
Shi, W.; Xiao, D.; Wang, L.; Dong, L.; Yan, Z.; Shen, Z.; Chen, S.; Chen, Y.; Zhao, W. Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy. Cell Death Dis., 2012, 3(3), e275.
[137]
Gwinn, D.M.; Shackelford, D.B.; Egan, D.F.; Mihaylova, M.M.; Mery, A.; Vasquez, D.S.; Turk, B.E.; Shaw, R.J. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell, 2008, 30(2), 214-226.
[138]
Cerezo, M.; Tichet, M.; Abbe, P.; Ohanna, M.; Lehraiki, A.; Rouaud, F.; Allegra, M.; Giacchero, D.; Bahadoran, P.; Bertolotto, C. Metformin blocks melanoma invasion and metastasis development in AMPK/p53-dependent manner. Mol. Cancer Ther., 2013, 12(8), 1605-1615.
[140]
Jones, R.G.; Plas, D.R.; Kubek, S.; Buzzai, M.; Mu, J.; Xu, Y.; Birnbaum, M.J.; Thompson, C.B. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell, 2005, 18(3), 283-293.
[141]
Xu, W.; Parmigiani, R.; Marks, P. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene, 2007, 26(37), 5541-5552.
[142]
Chipuk, J.E.; Kuwana, T.; Bouchier-Hayes, L.; Droin, N.M.; Newmeyer, D.D.; Schuler, M.; Green, D.R. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science, 2004, 303(5660), 1010-1014.
[143]
Condorelli, F.; Gnemmi, I.; Vallario, A.; Genazzani, A.; Canonico, P. Inhibitors of histone deacetylase (HDAC) restore the p53 pathway in neuroblastoma cells. Br. J. Pharmacol., 2008, 153(4), 657-668.
[144]
Bennett, M.; Macdonald, K.; Chan, S-W.; Luzio, J.P.; Simari, R.; Weissberg, P. Cell surface trafficking of Fas: A rapid mechanism of p53-mediated apoptosis. Science, 1998, 282(5387), 290-293.
[145]
Waring, P.; Müllbacher, A. Cell death induced by the Fas/Fas ligand pathway and its role in pathology. Immunol. Cell Biol., 1999, 77(4), 312-317.
[146]
Müller, M.; Wilder, S.; Bannasch, D.; Israeli, D.; Lehlbach, K.; Li-Weber, M.; Friedman, S.L.; Galle, P.R.; Stremmel, W.; Oren, M. p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J. Exp. Med., 1998, 188(11), 2033-2045.
[147]
Owen-Schaub, L.B.; Zhang, W.; Cusack, J.C.; Angelo, L.S.; Santee, S.M.; Fujiwara, T.; Roth, J.A.; Deisseroth, A.B.; Zhang, W-W.; Kruzel, E. Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol. Cell. Biol., 1995, 15(6), 3032-3040.
Related Books
Frontiers in Clinical Drug Research - Anti-Cancer Agents
NEOPLASIA and FERTILITY
Breast Cancer: Current Trends in Molecular Research
The Evolution of Radionanotargeting towards Clinical Precision Oncology: A Festschrift in Honor of Kalevi Kairemo
Nanotherapeutics for the Treatment of Hepatocellular Carcinoma
Topics in Anti-Cancer Research
Frontiers in Clinical Drug Research - Anti-Cancer Agents
Modern Cancer Therapies and Traditional Medicine: An Integrative Approach to Combat Cancers
Herbal Medicine: Back to the Future
Thrombosis in Cancer: A Medical Professional's Guide to Cancer Associated Thrombosis
Article Metrics
91
5