Generic placeholder image

Current Molecular Pharmacology


ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Research Article

Synergistic Effect of Epigenetic Inhibitors Decitabine and Suberoylanilide Hydroxamic Acid on Colorectal Cancer In vitro

Author(s): Sonia Abou Najem, Ghada Khawaja, Mohammad Hassan Hodroj and Sandra Rizk*

Volume 12, Issue 4, 2019

Page: [281 - 300] Pages: 20

DOI: 10.2174/1874467212666190313154531

Price: $65


Background: Colorectal Cancer (CRC) is a common cause of oncological deaths worldwide. Alterations of the epigenetic landscape constitute a well-documented hallmark of CRC phenotype. The accumulation of aberrant DNA methylation and histone acetylation plays a major role in altering gene activity and driving tumor onset, progression and metastasis.

Objective: In this study, we evaluated the effect of Suberoylanilide Hydroxamic Acid (SAHA), a panhistone deacetylase inhibitor, and Decitabine (DAC), a DNA methyltransferase inhibitor, either alone or in combination, on Caco-2 human colon cancer cell line in vitro.

Results: Our results showed that SAHA and DAC, separately, significantly decreased cell proliferation, induced apoptosis and cell cycle arrest of Caco-2 cell line. On the other hand, the sequential treatment of Caco-2 cells, first with DAC and then with SAHA, induced a synergistic anti-tumor effect with a significant enhancement of growth inhibition and apoptosis induction in Caco-2 cell line as compared to cells treated with either drug alone. Furthermore, the combination therapy upregulates protein expression levels of pro-apoptotic proteins Bax, p53 and cytochrome c, downregulates the expression of antiapoptotic Bcl-2 protein and increases the cleavage of procaspases 8 and 9; this suggests that the combination activates apoptosis via both the intrinsic and extrinsic pathways. Mechanistically, we demonstrated that the synergistic anti-neoplastic activity of combined SAHA and DAC involves an effect on PI3K/AKT and Wnt/β-catenin signaling.

Conclusion: In conclusion, our results provide evidence for the profound anti-tumorigenic effect of sequentially combined SAHA and DAC in the CRC cell line and offer new insights into the corresponding underlined molecular mechanism.

Keywords: Apoptosis, epigenetics, colon cancer, decitabine, suberoylanilide hydroxamic acid, in vitro.

Graphical Abstract
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2015. CA Cancer J. Clin., 2015, 65(1), 5-29.
[] [PMID: 25559415]
Brenner, H.; Kloor, M.; Pox, C.P. Colorectal cancer. Lancet, 2014, 383(9927), 1490-1502.
[] [PMID: 24225001]
van Engeland, M.; Derks, S.; Smits, K.M.; Meijer, G.A.; Herman, J.G. Colorectal cancer epigenetics: complex simplicity. J. Clin. Oncol., 2011, 29(10), 1382-1391.
[] [PMID: 21220596]
Verma, M.; Kumar, V. Epigenetic Biomarkers in Colorectal Cancer. Mol. Diagn. Ther., 2017, 21(2), 153-165.
[] [PMID: 27878475]
Hinoue, T.; Weisenberger, D.J.; Lange, C.P.; Shen, H.; Byun, H.M.; Van Den Berg, D.; Malik, S.; Pan, F.; Noushmehr, H.; van Dijk, C.M.; Tollenaar, R.A.; Laird, P.W. Genome-scale analysis of aberrant DNA methylation in colorectal cancer. Genome Res., 2012, 22(2), 271-282.
[] [PMID: 21659424]
Fahrner, J.A.; Eguchi, S.; Herman, J.G.; Baylin, S.B. Dependence of histone modifications and gene expression on DNA hypermethylation in cancer. Cancer Res., 2002, 62(24), 7213-7218.
[PMID: 12499261]
El-Osta, A.; Wolffe, A.P. DNA methylation and histone deacetylation in the control of gene expression: basic biochemistry to human development and disease. Gene Expr., 2000, 9(1-2), 63-75.
[PMID: 11097425]
Nan, X.; Ng, H.H.; Johnson, C.A.; Laherty, C.D.; Turner, B.M.; Eisenman, R.N.; Bird, A. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature, 1998, 393(6683), 386-389.
[] [PMID: 9620804]
Ou, J.N.; Torrisani, J.; Unterberger, A.; Provençal, N.; Shikimi, K.; Karimi, M.; Ekström, T.J.; Szyf, M. Histone deacetylase inhibitor Trichostatin A induces global and gene-specific DNA demethylation in human cancer cell lines. Biochem. Pharmacol., 2007, 73(9), 1297-1307.
[] [PMID: 17276411]
Yang, F.; Zhang, L.; Li, J.; Huang, J.; Wen, R.; Ma, L.; Zhou, D.; Li, L. Trichostatin A and 5-azacytidine both cause an increase in global histone H4 acetylation and a decrease in global DNA and H3K9 methylation during mitosis in maize. BMC Plant Biol., 2010, 10, 178-189.
[] [PMID: 20718950]
Bachman, K.E.; Park, B.H.; Rhee, I.; Rajagopalan, H.; Herman, J.G.; Baylin, S.B.; Kinzler, K.W.; Vogelstein, B. Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell, 2003, 3(1), 89-95.
[] [PMID: 12559178]
Christman, J.K. 5-Azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene, 2002, 21(35), 5483-5495.
[] [PMID: 12154409]
Ishiguro, M.; Iida, S.; Uetake, H.; Morita, S.; Makino, H.; Kato, K.; Takagi, Y.; Enomoto, M.; Sugihara, K. Effect of combined therapy with low-dose 5-aza-2′-deoxycytidine and irinotecan on colon cancer cell line HCT-15. Ann. Surg. Oncol., 2007, 14(5), 1752-1762.
[] [PMID: 17195906]
Yang, D.; Torres, C.M.; Bardhan, K.; Zimmerman, M.; McGaha, T.L.; Liu, K. Decitabine and vorinostat cooperate to sensitize colon carcinoma cells to Fas ligand-induced apoptosis in vitro and tumor suppression in vivo. J. Immunol., 2012, 188(9), 4441-4449.
[] [PMID: 22461695]
Plumb, J.A.; Strathdee, G.; Sludden, J.; Kaye, S.B.; Brown, R. Reversal of drug resistance in human tumor xenografts by 2′-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res., 2000, 60(21), 6039-6044.
[PMID: 11085525]
Samlowski, W.E.; Leachman, S.A.; Wade, M.; Cassidy, P.; Porter-Gill, P.; Busby, L.; Wheeler, R.; Boucher, K.; Fitzpatrick, F.; Jones, D.A.; Karpf, A.R. Evaluation of a 7-day continuous intravenous infusion of decitabine: inhibition of promoter-specific and global genomic DNA methylation. J. Clin. Oncol., 2005, 23(17), 3897-3905.
[] [PMID: 15753459]
Aparicio, A.; Eads, C.A.; Leong, L.A.; Laird, P.W.; Newman, E.M.; Synold, T.W.; Baker, S.D.; Zhao, M.; Weber, J.S. Phase I trial of continuous infusion 5-aza-2′-deoxycytidine. Cancer Chemother. Pharmacol., 2003, 51(3), 231-239.
[PMID: 12655442]
Sun, P.C.; Tzao, C.; Chen, B.H.; Liu, C.W.; Yu, C.P.; Jin, J.S. Suberoylanilide hydroxamic acid induces apoptosis and sub-G1 arrest of 320 HSR colon cancer cells. J. Biomed. Sci., 2010, 17, 76-85.
[] [PMID: 20846458]
Marks, P.; Rifkind, R.A.; Richon, V.M.; Breslow, R.; Miller, T.; Kelly, W.K. Histone deacetylases and cancer: causes and therapies. Nat. Rev. Cancer, 2001, 1(3), 194-202.
[] [PMID: 11902574]
Olsen, E.A.; Kim, Y.H.; Kuzel, T.M.; Pacheco, T.R.; Foss, F.M.; Parker, S.; Frankel, S.R.; Chen, C.; Ricker, J.L.; Arduino, J.M.; Duvic, M. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J. Clin. Oncol., 2007, 25(21), 3109-3115.
[] [PMID: 17577020]
Lobjois, V.; Frongia, C.; Jozan, S.; Truchet, I.; Valette, A. Cell cycle and apoptotic effects of SAHA are regulated by the cellular microenvironment in HCT116 multicellular tumour spheroids. Eur. J. Cancer, 2009, 45(13), 2402-2411.
[] [PMID: 19553104]
Hsi, L.C.; Xi, X.; Lotan, R.; Shureiqi, I.; Lippman, S.M. The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces apoptosis via induction of 15-lipoxygenase-1 in colorectal cancer cells. Cancer Res., 2004, 64(23), 8778-8781.
[] [PMID: 15574791]
Munster, P.N.; Troso-Sandoval, T.; Rosen, N.; Rifkind, R.; Marks, P.A.; Richon, V.M. The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells. Cancer Res., 2001, 61(23), 8492-8497.
[PMID: 11731433]
Butler, L.M.; Agus, D.B.; Scher, H.I.; Higgins, B.; Rose, A.; Cordon-Cardo, C.; Thaler, H.T.; Rifkind, R.A.; Marks, P.A.; Richon, V.M. Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res., 2000, 60(18), 5165-5170.
[PMID: 11016644]
Clevers, H.; Nusse, R. Wnt/β-catenin signaling and disease. Cell, 2012, 149(6), 1192-1205.
[] [PMID: 22682243]
Aberle, H.; Bauer, A.; Stappert, J.; Kispert, A.; Kemler, R. beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J., 1997, 16(13), 3797-3804.
[] [PMID: 9233789]
Kitagawa, M.; Hatakeyama, S.; Shirane, M.; Matsumoto, M.; Ishida, N.; Hattori, K.; Nakamichi, I.; Kikuchi, A.; Nakayama, K.; Nakayama, K. An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin. EMBO J., 1999, 18(9), 2401-2410.
[] [PMID: 10228155]
Comprehensive molecular characterization of human colon and rectal cancer. Nature, 2012, 487(7407), 330-337.
[] [PMID: 22810696]
Schatoff, E.M.; Leach, B.I.; Dow, L.E. Wnt Signaling and Colorectal Cancer. Curr. Colorectal Cancer Rep., 2017, 13(2), 101-110.
[] [PMID: 28413363]
Qi, J.; Zhu, Y.Q.; Luo, J.; Tao, W.H. Hypermethylation and expression regulation of secreted frizzled-related protein genes in colorectal tumor. World J. Gastroenterol., 2006, 12(44), 7113-7117.
[] [PMID: 17131472]
Rawson, J.B.; Manno, M.; Mrkonjic, M.; Daftary, D.; Dicks, E.; Buchanan, D.D.; Younghusband, H.B.; Parfrey, P.S.; Young, J.P.; Pollett, A.; Green, R.C.; Gallinger, S.; McLaughlin, J.R.; Knight, J.A.; Bapat, B. Promoter methylation of Wnt antagonists DKK1 and SFRP1 is associated with opposing tumor subtypes in two large populations of colorectal cancer patients. Carcinogenesis, 2011, 32(5), 741-747.
[] [PMID: 21304055]
Esteller, M.; Sparks, A.; Toyota, M.; Sanchez-Cespedes, M.; Capella, G.; Peinado, M.A.; Gonzalez, S.; Tarafa, G.; Sidransky, D.; Meltzer, S.J.; Baylin, S.B.; Herman, J.G. Analysis of adenomatous polyposis coli promoter hypermethylation in human cancer. Cancer Res., 2000, 60(16), 4366-4371.
[PMID: 10969779]
Sheng, H.; Shao, J.; Townsend, C.M., Jr; Evers, B.M. Phosphatidylinositol 3-kinase mediates proliferative signals in intestinal epithelial cells. Gut, 2003, 52(10), 1472-1478.
[] [PMID: 12970141]
Samuels, Y.; Ericson, K. Oncogenic PI3K and its role in cancer. Curr. Opin. Oncol., 2006, 18(1), 77-82.
[] [PMID: 16357568]
Lin, P.C.; Lin, J.K.; Lin, H.H.; Lan, Y.T.; Lin, C.C.; Yang, S.H.; Chen, W.S.; Liang, W.Y.; Jiang, J.K.; Chang, S.C. A comprehensive analysis of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) loss in colorectal cancer. World J. Surg. Oncol., 2015, 13, 186-193.
[] [PMID: 25986931]
Maehama, T.; Dixon, J.E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem., 1998, 273(22), 13375-13378.
[] [PMID: 9593664]
Song, M.S.; Salmena, L.; Pandolfi, P.P. The functions and regulation of the PTEN tumour suppressor. Nat. Rev. Mol. Cell Biol., 2012, 13(5), 283-296.
[] [PMID: 22473468]
Lamberti, C.; Lin, K.M.; Yamamoto, Y.; Verma, U.; Verma, I.M.; Byers, S.; Gaynor, R.B. Regulation of beta-catenin function by the IkappaB kinases. J. Biol. Chem., 2001, 276(45), 42276-42286.
[] [PMID: 11527961]
Fang, D.; Hawke, D.; Zheng, Y.; Xia, Y.; Meisenhelder, J.; Nika, H.; Mills, G.B.; Kobayashi, R.; Hunter, T.; Lu, Z. Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity. J. Biol. Chem., 2007, 282(15), 11221-11229.
[] [PMID: 17287208]
Agarwal, A.; Das, K.; Lerner, N.; Sathe, S.; Cicek, M.; Casey, G.; Sizemore, N. The AKT/I kappa B kinase pathway promotes angiogenic/metastatic gene expression in colorectal cancer by activating nuclear factor-kappa B and beta-catenin. Oncogene, 2005, 24(6), 1021-1031.
[] [PMID: 15592509]
Lao, V.V.; Grady, W.M. Epigenetics and colorectal cancer. Nat. Rev. Gastroenterol. Hepatol., 2011, 8(12), 686-700.
[] [PMID: 22009203]
Jones, P.A.; Baylin, S.B. The epigenomics of cancer. Cell, 2007, 128(4), 683-692.
[] [PMID: 17320506]
Baylin, S.B.; Herman, J.G.; Graff, J.R.; Vertino, P.M.; Issa, J.P. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv. Cancer Res., 1998, 72, 141-196.
[] [PMID: 9338076]
Baylin, S.B.; Ohm, J.E. Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction? Nat. Rev. Cancer, 2006, 6(2), 107-116.
[] [PMID: 16491070]
Weichert, W.; Röske, A.; Niesporek, S.; Noske, A.; Buckendahl, A.C.; Dietel, M.; Gekeler, V.; Boehm, M.; Beckers, T.; Denkert, C. Class I histone deacetylase expression has independent prognostic impact in human colorectal cancer: specific role of class I histone deacetylases in vitro and in vivo. Clin. Cancer Res., 2008, 14(6), 1669-1677.
[] [PMID: 18347167]
Wilson, A.J.; Byun, D.S.; Popova, N.; Murray, L.B.; L’Italien, K.; Sowa, Y.; Arango, D.; Velcich, A.; Augenlicht, L.H.; Mariadason, J.M. Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer. J. Biol. Chem., 2006, 281(19), 13548-13558.
[] [PMID: 16533812]
Nakagawa, M.; Oda, Y.; Eguchi, T.; Aishima, S.; Yao, T.; Hosoi, F.; Basaki, Y.; Ono, M.; Kuwano, M.; Tanaka, M.; Tsuneyoshi, M. Expression profile of class I histone deacetylases in human cancer tissues. Oncol. Rep., 2007, 18(4), 769-774.
[] [PMID: 17786334]
Ishihama, K.; Yamakawa, M.; Semba, S.; Takeda, H.; Kawata, S.; Kimura, S.; Kimura, W. Expression of HDAC1 and CBP/p300 in human colorectal carcinomas. J. Clin. Pathol., 2007, 60(11), 1205-1210.
[] [PMID: 17720775]
Mariadason, J.M. HDACs and HDAC inhibitors in colon cancer. Epigenetics, 2008, 3(1), 28-37.
[] [PMID: 18326939]
Grant, S.; Easley, C.; Kirkpatrick, P. Vorinostat. Nat. Rev. Drug Discov., 2007, 6(1), 21-22.
[] [PMID: 17269160]
Stresemann, C.; Lyko, F. Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int. J. Cancer, 2008, 123(1), 8-13.
[] [PMID: 18425818]
Momparler, R.L. Pharmacology of 5-Aza-2′-deoxycytidine (decitabine). Semin. Hematol., 2005, 42(3)(Suppl. 2), S9-S16.
[] [PMID: 16015507]
Jin, J.S.; Tsao, T.Y.; Sun, P.C.; Yu, C.P.; Tzao, C. SAHA inhibits the growth of colon tumors by decreasing histone deacetylase and the expression of cyclin D1 and survivin. Pathol. Oncol. Res., 2012, 18(3), 713-720.
[] [PMID: 22270866]
Alzoubi, S.; Brody, L.; Rahman, S.; Mahul-Mellier, A.L.; Mercado, N.; Ito, K.; El-Bahrawy, M.; Silver, A.; Boobis, A.; Bell, J.D.; Hajji, N. Synergy between histone deacetylase inhibitors and DNA-damaging agents is mediated by histone deacetylase 2 in colorectal cancer. Oncotarget, 2016, 7(28), 44505-44521.
[] [PMID: 27283986]
Stresemann, C.; Brueckner, B.; Musch, T.; Stopper, H.; Lyko, F. Functional diversity of DNA methyltransferase inhibitors in human cancer cell lines. Cancer Res., 2006, 66(5), 2794-2800.
[] [PMID: 16510601]
Cowan, L.A.; Talwar, S.; Yang, A.S. Will DNA methylation inhibitors work in solid tumors? A review of the clinical experience with azacitidine and decitabine in solid tumors. Epigenomics, 2010, 2(1), 71-86.
[] [PMID: 22122748]
Grabarska, A.; Łuszczki, J.J.; Nowosadzka, E.; Gumbarewicz, E.; Jeleniewicz, W.; Dmoszyńska-Graniczka, M.; Kowalczuk, K.; Kupisz, K.; Polberg, K.; Stepulak, A. Histone Deacetylase Inhibitor SAHA as Potential Targeted Therapy Agent for Larynx Cancer Cells. J. Cancer, 2017, 8(1), 19-28.
[] [PMID: 28123594]
Kumagai, T.; Wakimoto, N.; Yin, D.; Gery, S.; Kawamata, N.; Takai, N.; Komatsu, N.; Chumakov, A.; Imai, Y.; Koeffler, H.P. Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (Vorinostat, SAHA) profoundly inhibits the growth of human pancreatic cancer cells. Int. J. Cancer, 2007, 121(3), 656-665.
[] [PMID: 17417771]
Gartel, A.L.; Radhakrishnan, S.K. Lost in transcription: p21 repression, mechanisms, and consequences. Cancer Res., 2005, 65(10), 3980-3985.
[] [PMID: 15899785]
Ford, H.L.; Pardee, A.B. Cancer and the cell cycle. J. Cell. Biochem., 1999, 33(Suppl. 32), 166-172.
[<166:AID-JCB20>3.0.CO;2-J] [PMID: 10629116]
Gui, C.Y.; Ngo, L.; Xu, W.S.; Richon, V.M.; Marks, P.A. Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc. Natl. Acad. Sci. USA, 2004, 101(5), 1241-1246.
[] [PMID: 14734806]
Shi, X.Y.; Ding, W.; Li, T.Q.; Zhang, Y.X.; Zhao, S.C. Histone Deacetylase (HDAC) Inhibitor, Suberoylanilide Hydroxamic Acid (SAHA), Induces Apoptosis in Prostate Cancer Cell Lines via the Akt/FOXO3a Signaling Pathway. Med. Sci. Monit., 2017, 23, 5793-5802.
[] [PMID: 29211704]
Shin, D.Y.; Sung Kang, H.; Kim, G.Y.; Kim, W.J.; Yoo, Y.H.; Choi, Y.H. Decitabine, a DNA methyltransferases inhibitor, induces cell cycle arrest at G2/M phase through p53-independent pathway in human cancer cells. Biomed. Pharmacother., 2013, 67(4), 305-311.
[] [PMID: 23582784]
Yam, C.H.; Fung, T.K.; Poon, R.Y. Cyclin A in cell cycle control and cancer. Cell. Mol. Life Sci., 2002, 59(8), 1317-1326.
[] [PMID: 12363035]
Lavelle, D.; DeSimone, J.; Hankewych, M.; Kousnetzova, T.; Chen, Y.H. Decitabine induces cell cycle arrest at the G1 phase via p21(WAF1) and the G2/M phase via the p38 MAP kinase pathway. Leuk. Res., 2003, 27(11), 999-1007.
[] [PMID: 12859993]
Hollenbach, P.W.; Nguyen, A.N.; Brady, H.; Williams, M.; Ning, Y.; Richard, N.; Krushel, L.; Aukerman, S.L.; Heise, C.; MacBeth, K.J. A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One, 2010, 5(2)e9001
[] [PMID: 20126405]
Yamamoto, S.; Tanaka, K.; Sakimura, R.; Okada, T.; Nakamura, T.; Li, Y.; Takasaki, M.; Nakabeppu, Y.; Iwamoto, Y. Suberoylanilide hydroxamic acid (SAHA) induces apoptosis or autophagy-associated cell death in chondrosarcoma cell lines. Anticancer Res., 2008, 28(3A), 1585-1591.
[PMID: 18630516]
Sun, P.C.; Tzao, C.; Chen, B.H.; Liu, C.W.; Yu, C.P.; Jin, J.S. Suberoylanilide hydroxamic acid induces apoptosis and sub-G1 arrest of 320 HSR colon cancer cells. J. Biomed. Sci., 2010, 17, 76-89.
[] [PMID: 20846458]
Shao, Y.; Gao, Z.; Marks, P.A.; Jiang, X. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc. Natl. Acad. Sci. USA, 2004, 101(52), 18030-18035.
[] [PMID: 15596714]
Bolden, J.E.; Shi, W.; Jankowski, K.; Kan, C.Y.; Cluse, L.; Martin, B.P.; MacKenzie, K.L.; Smyth, G.K.; Johnstone, R.W. HDAC inhibitors induce tumor-cell-selective pro-apoptotic transcriptional responses. Cell Death Dis., , 2013, 4e519.
[] [PMID: 23449455]
Shin, D.Y.; Park, Y.S.; Yang, K.; Kim, G.Y.; Kim, W.J.; Han, M.H.; Kang, H.S.; Choi, Y.H. Decitabine, a DNA methyltransferase inhibitor, induces apoptosis in human leukemia cells through intracellular reactive oxygen species generation. Int. J. Oncol., 2012, 41(3), 910-918.
[] [PMID: 22767021]
Lin, J.; Lai, M.; Huang, Q.; Ruan, W.; Ma, Y.; Cui, J. Reactivation of IGFBP7 by DNA demethylation inhibits human colon cancer cell growth in vitro. Cancer Biol. Ther., 2008, 7(12), 1896-1900.
[] [PMID: 18981723]
Hsi, L.C.; Xi, X.; Wu, Y.; Lippman, S.M. The methyltransferase inhibitor 5-aza-2-deoxycytidine induces apoptosis via induction of 15-lipoxygenase-1 in colorectal cancer cells. Mol. Cancer Ther., 2005, 4(11), 1740-1746.
[] [PMID: 16275995]
Luszczek, W.; Cheriyath, V.; Mekhail, T.M.; Borden, E.C. Combinations of DNA methyltransferase and histone deacetylase inhibitors induce DNA damage in small cell lung cancer cells: correlation of resistance with IFN-stimulated gene expression. Mol. Cancer Ther., 2010, 9(8), 2309-2321.
[] [PMID: 20682643]
Pera, B.; Tang, T.; Marullo, R.; Yang, S.N.; Ahn, H.; Patel, J.; Elstrom, R.; Ruan, J.; Furman, R.; Leonard, J.; Cerchietti, L.; Martin, P. Combinatorial epigenetic therapy in diffuse large B cell lymphoma pre-clinical models and patients. Clin. Epigenetics, 2016, 8, 79-89.
[] [PMID: 27453763]
Kalac, M.; Scotto, L.; Marchi, E.; Amengual, J.; Seshan, V.E.; Bhagat, G.; Ulahannan, N.; Leshchenko, V.V.; Temkin, A.M.; Parekh, S.; Tycko, B.; O’Connor, O.A. HDAC inhibitors and decitabine are highly synergistic and associated with unique gene-expression and epigenetic profiles in models of DLBCL. Blood, 2011, 118(20), 5506-5516.
[] [PMID: 21772049]
Chen, M.Y.; Liao, W.S.; Lu, Z.; Bornmann, W.G.; Hennessey, V.; Washington, M.N.; Rosner, G.L.; Yu, Y.; Ahmed, A.A.; Bast, R.C., Jr Decitabine and suberoylanilide hydroxamic acid (SAHA) inhibit growth of ovarian cancer cell lines and xenografts while inducing expression of imprinted tumor suppressor genes, apoptosis, G2/M arrest, and autophagy. Cancer, 2011, 117(19), 4424-4438.
[] [PMID: 21491416]
Stathis, A.; Hotte, S.J.; Chen, E.X.; Hirte, H.W.; Oza, A.M.; Moretto, P.; Webster, S.; Laughlin, A.; Stayner, L.A.; McGill, S.; Wang, L.; Zhang, W.J.; Espinoza-Delgado, I.; Holleran, J.L.; Egorin, M.J.; Siu, L.L. Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin’s lymphomas. Clin. Cancer Res., 2011, 17(6), 1582-1590.
[] [PMID: 21278245]
Young, C.S.; Clarke, K.M.; Kettyle, L.M.; Thompson, A.; Mills, K.I. Decitabine-Vorinostat combination treatment in acute myeloid leukemia activates pathways with potential for novel triple therapy. Oncotarget, 2017, 8(31), 51429-51446.
[] [PMID: 28881658]
Jones, P.L.; Veenstra, G.J.; Wade, P.A.; Vermaak, D.; Kass, S.U.; Landsberger, N.; Strouboulis, J.; Wolffe, A.P. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat. Genet., 1998, 19(2), 187-191.
[] [PMID: 9620779]
Arzenani, M.K.; Zade, A.E.; Ming, Y.; Vijverberg, S.J.; Zhang, Z.; Khan, Z.; Sadique, S.; Kallenbach, L.; Hu, L.; Vukojević, V.; Ekström, T.J. Genomic DNA hypomethylation by histone deacetylase inhibition implicates DNMT1 nuclear dynamics. Mol. Cell. Biol., 2011, 31(19), 4119-4128.
[] [PMID: 21791605]
Gius, D.; Cui, H.; Bradbury, C.M.; Cook, J.; Smart, D.K.; Zhao, S.; Young, L.; Brandenburg, S.A.; Hu, Y.; Bisht, K.S.; Ho, A.S.; Mattson, D.; Sun, L.; Munson, P.J.; Chuang, E.Y.; Mitchell, J.B.; Feinberg, A.P. Distinct effects on gene expression of chemical and genetic manipulation of the cancer epigenome revealed by a multimodality approach. Cancer Cell, 2004, 6(4), 361-371.
[] [PMID: 15488759]
Momparler, R.L.; Côté, S.; Momparler, L.F.; Idaghdour, Y. Epigenetic therapy of acute myeloid leukemia using 5-aza-2′-deoxycytidine (decitabine) in combination with inhibitors of histone methylation and deacetylation. Clin. Epigenetics, 2014, 6(1), 19-31.
[] [PMID: 25313314]
Si, J.; Boumber, Y.A.; Shu, J.; Qin, T.; Ahmed, S.; He, R.; Jelinek, J.; Issa, J.P. Chromatin remodeling is required for gene reactivation after decitabine-mediated DNA hypomethylation. Cancer Res., 2010, 70(17), 6968-6977.
[] [PMID: 20713525]
Paul, T.A.; Bies, J.; Small, D.; Wolff, L. Signatures of polycomb repression and reduced H3K4 trimethylation are associated with p15INK4b DNA methylation in AML. Blood, 2010, 115(15), 3098-3108.
[] [PMID: 20190193]
Flotho, C.; Claus, R.; Batz, C.; Schneider, M.; Sandrock, I.; Ihde, S.; Plass, C.; Niemeyer, C.M.; Lübbert, M. The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia, 2009, 23(6), 1019-1028.
[] [PMID: 19194470]
Zhou, Q.; Agoston, A.T.; Atadja, P.; Nelson, W.G.; Davidson, N.E. Inhibition of histone deacetylases promotes ubiquitin-dependent proteasomal degradation of DNA methyltransferase 1 in human breast cancer cells. Mol. Cancer Res., 2008, 6(5), 873-883.
[] [PMID: 18505931]
Burris, H.A., III Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway. Cancer Chemother. Pharmacol., 2013, 71(4), 829-842.
[] [PMID: 23377372]
Malinowsky, K.; Nitsche, U.; Janssen, K.P.; Bader, F.G.; Späth, C.; Drecoll, E.; Keller, G.; Höfler, H.; Slotta-Huspenina, J.; Becker, K.F. Activation of the PI3K/AKT pathway correlates with prognosis in stage II colon cancer. Br. J. Cancer, 2014, 110(8), 2081-2089.
[] [PMID: 24619078]
Vredeveld, L.C.; Possik, P.A.; Smit, M.A.; Meissl, K.; Michaloglou, C.; Horlings, H.M.; Ajouaou, A.; Kortman, P.C.; Dankort, D.; McMahon, M.; Mooi, W.J.; Peeper, D.S. Abrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesis. Genes Dev., 2012, 26(10), 1055-1069.
[] [PMID: 22549727]
Pandurangan, A.K. Potential targets for prevention of colorectal cancer: a focus on PI3K/Akt/mTOR and Wnt pathways. Asian Pac. J. Cancer Prev., 2013, 14(4), 2201-2205.
[] [PMID: 23725112]
Lee, J.O.; Yang, H.; Georgescu, M.M.; Di Cristofano, A.; Maehama, T.; Shi, Y.; Dixon, J.E.; Pandolfi, P.; Pavletich, N.P. Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell, 1999, 99(3), 323-334.
[] [PMID: 10555148]
Chalhoub, N.; Baker, S.J. PTEN and the PI3-kinase pathway in cancer. Annu. Rev. Pathol., 2009, 4, 127-150.
[] [PMID: 18767981]
Zhang, S.; Yu, D. PI(3)king apart PTEN’s role in cancer. Clin. Cancer Res., 2010, 16(17), 4325-4330.
[] [PMID: 20622047]
Zhan, T.; Rindtorff, N.; Boutros, M. Wnt signaling in cancer. Oncogene, 2017, 36(11), 1461-1473.
[] [PMID: 27617575]
Liu, C.; Li, Y.; Semenov, M.; Han, C.; Baeg, G.H.; Tan, Y.; Zhang, Z.; Lin, X.; He, X. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell, 2002, 108(6), 837-847.
[] [PMID: 11955436]
Doble, B.W.; Patel, S.; Wood, G.A.; Kockeritz, L.K.; Woodgett, J.R. Functional redundancy of GSK-3alpha and GSK-3beta in Wnt/beta-catenin signaling shown by using an allelic series of embryonic stem cell lines. Dev. Cell, 2007, 12(6), 957-971.
[] [PMID: 17543867]
Verheyen, E.M.; Gottardi, C.J. Regulation of Wnt/beta-catenin signaling by protein kinases. Dev. Dyn., 2010, 239(1), 34-44.
[PMID: 19623618]
Hart, M.; Concordet, J.P.; Lassot, I.; Albert, I.; del los Santos, R.; Durand, H.; Perret, C.; Rubinfeld, B.; Margottin, F.; Benarous, R.; Polakis, P. The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell. Curr. Biol., 1999, 9(4), 207-210.
[] [PMID: 10074433]
Sutherland, C.; Leighton, I.A.; Cohen, P. Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling. Biochem. J., 1993, 296(Pt 1), 15-19.
[] [PMID: 8250835]
Frame, S.; Cohen, P.; Biondi, R.M. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol. Cell, 2001, 7(6), 1321-1327.
[] [PMID: 11430833]
Cole, A.; Frame, S.; Cohen, P. Further evidence that the tyrosine phosphorylation of glycogen synthase kinase-3 (GSK3) in mammalian cells is an autophosphorylation event. Biochem. J., 2004, 377(Pt 1), 249-255.
[] [PMID: 14570592]
Silva, A.L.; Dawson, S.N.; Arends, M.J.; Guttula, K.; Hall, N.; Cameron, E.A.; Huang, T.H.; Brenton, J.D.; Tavaré, S.; Bienz, M.; Ibrahim, A.E. Boosting Wnt activity during colorectal cancer progression through selective hypermethylation of Wnt signaling antagonists. BMC Cancer, 2014, 14, 891-901.
[] [PMID: 25432628]
Wang, X.; Meng, X.; Sun, X.; Liu, M.; Gao, S.; Zhao, J.; Pei, F.; Yu, H. Wnt/beta-catenin signaling pathway may regulate cell cycle and expression of cyclin A and cyclin E protein in hepatocellular carcinoma cells. Cell Cycle, 2009, 8(10), 1567-1570.
[] [PMID: 19411833]
Park, C.S.; Kim, S.I.; Lee, M.S.; Youn, C.Y.; Kim, D.J.; Jho, E.H.; Song, W.K. Modulation of beta-catenin phosphorylation/degradation by cyclin-dependent kinase 2. J. Biol. Chem., 2004, 279(19), 19592-19599.
[] [PMID: 14985333]

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy