Enhanced cytotoxicity of human hepatocellular carcinoma cells following pretreatment with sorafenib combined with trichostatin A

Chen,John  Chun‑Hao; Chuang,Hui‑Yen; Liao,Yi‑Jen; Hsu,Fei‑Ting; Chen,Yen‑Chung; Wang,Wei‑Hsun; Hwang,Jeng‑Jong

doi:10.3892/ol.2018.9582

Enhanced cytotoxicity of human hepatocellular carcinoma cells following pretreatment with sorafenib combined with trichostatin A

Authors:
- John Chun‑Hao Chen
- Hui‑Yen Chuang
- Yi‑Jen Liao
- Fei‑Ting Hsu
- Yen‑Chung Chen
- Wei‑Hsun Wang
- Jeng‑Jong Hwang
View Affiliations

Affiliations: Department of Biomedical Imaging and Radiological Sciences, National Yang Ming University, Taipei 112, Taiwan, R.O.C., School of Medical Laboratory and Biotechnology, Taipei Medical University, Taipei 110, Taiwan, R.O.C., Department of Medical Imaging, Taipei Medical University Hospital, Taipei 110, Taiwan, R.O.C., Department of Pathology, National Yang Ming University Hospital, Yilan 260, Taiwan, R.O.C., Department of Orthopedic Surgery, Changhua Christian Hospital, Changhua 500, Taiwan, R.O.C.
Published online on: October 16, 2018 https://doi.org/10.3892/ol.2018.9582
Pages: 638-645

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Trichostatin A (TSA), a hydroxamate histone deacetylase inhibitor, is a compound that has been identified to induce anticancer activity. The aim of the present study was to investigate whether sorafenib, in combination with TSA, was able to augment the anticancer effects of TSA, identifying an optimum treatment time plan and the potential underlying molecular mechanisms involved in human hepatocellular carcinoma (HCC) in vitro. Huh7/nuclear factor‑κB (NF‑κB)‑luc2 cells were treated with TSA or sorafenib alone, or sorafenib, prior to, in combination with or following TSA treatment. Huh7/NF‑κB‑luc2 cell viability following TSA treatment was determined using an MTT assay, and NF‑κB activity was analyzed. In addition, the expression levels of NF‑κB‑regulated downstream effector proteins were assayed by western blotting. Inhibitors of mitogen‑activated protein kinases (MAPKs), protein kinase B (AKT) and mutant inhibitor of NF‑κBα (IκBαM) vectors were used to confirm the function of the NF‑κB signal transduction pathways in response to the effects of sorafenib combined with TSA against HCC. The results of the present study indicated that pre‑treatment with sorafenib followed by TSA inhibited the cell viability compared with other treatment modalities, and prevented TSA‑induced extracellular‑signal‑regulated kinase (ERK)/NF‑κB activity and expression of downstream effector proteins. It was further demonstrated that IκBαM vector sensitized Huh7/NF‑κB‑luc2 cells to TSA, thus it was possible to reverse TSA‑induced NF‑κB activity using PD98059, a MAPK/ERK kinase inhibitor. In conclusion, sorafenib pre‑treatment may increase the efficacy of subsequent TSA treatment in HCC. Furthermore, sorafenib pre‑treatment is hypothesized to sensitize HCC to TSA via the inhibition of the MEK/ERK/NF‑κB signal transduction pathway.

View Figures

View References

1	Pan LN, Lu J and Huang B: HDAC inhibitors: A potential new category of anti-tumor agents. Cell Mol Immunol. 4:337–343. 2007.PubMed/NCBI
2	Mund C and Lyko F: Epigenetic cancer therapy: Proof of concept and remaining challenges. Bioessays. 32:949–957. 2010. View Article : Google Scholar : PubMed/NCBI
3	Rosato RR, Almenara JA and 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. 63:3637–3645. 2003.PubMed/NCBI
4	Baradari V, Höpfner M, Huether A, Schuppan D and Scherubl H: Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells. World J Gastroenterol. 13:4458–4466. 2007. View Article : Google Scholar : PubMed/NCBI
5	Ngamphaiboon N, Dy GK, Ma WW, Zhao Y, Reungwetwattana T, DePaolo D, Ding Y, Brady W, Fetterly G and Adjei AA: A phase I study of the histone deacetylase (HDAC) inhibitor entinostat, in combination with sorafenib in patients with advanced solid tumors. Invest New Drugs. 33:225–232. 2015. View Article : Google Scholar : PubMed/NCBI
6	Yuan H, Li AJ, Ma SL, Cui LJ, Wu B, Yin L and Wu MC: Inhibition of autophagy significantly enhances combination therapy with sorafenib and HDAC inhibitors (vorinostatin) for human hepatoma cells. World J Gastroenterol. 20:4953–4962. 2014. View Article : Google Scholar : PubMed/NCBI
7	Huang HL, Lee HY, Tsai AC, Peng CY, Lai MJ, Wang JC, Pan SL, Teng CM and Liou JP: Anticancer activity of MPT0E028, a novel potent histone deacetylase inhibitor, in human colorectal cancer HCT116 cells in vitro and in vivo. PLoS One. 7:e436452012. View Article : Google Scholar : PubMed/NCBI
8	Chen CH, Chen MC, Wang JC, Tsai AC, Chen CS, Liou JP, Pan SL and Teng CM: Synergistic interaction between the HDAC inhibitor, MPT0E028 and sorafenib in liver cancer cells in vitro and in vivo. Clin Cancer Res. 20:1274–1287. 2014. View Article : Google Scholar : PubMed/NCBI
9	Yao J, Duan L, Fan M and Wu X: NF-kappaB signaling pathway is involved in growth inhibition, G2/M arrest and apoptosis induced by trichostatin A in human tongue carcinoma cells. Pharmaco Res. 54:406–413. 2006.
10	Zhang G, Park MA, Mitchell C, Hamed H, Rahmani M, Martin AP, Curiel DT, Yacoub A, Graf M, Lee R, et al: Vorinostat and sorafenib synergistically kill tumor cells via FLIP suppression and CD95 activation. Clin Cancer Res. 14:5385–5399. 2008. View Article : Google Scholar : PubMed/NCBI
11	Duvic M and Vu J: Update on the treatment of cutaneous T-cell lymphoma (CTCL): Focus on vorinostat. Biol Targets Ther. 1:377–392. 2007.
12	Coradini D and Speranza A: Histone deacetylase inhibitors for treatment of hepatocellular carcinoma. Acta pharmacol Sin. 26:1025–1033. 2005. View Article : Google Scholar : PubMed/NCBI
13	Yan G, Graham K and Lanza-Jacoby S: Curcumin enhances the anticancer effects of trichostatin a in breast cancer cells. Mol Carcinogen. 52:404–411. 2013. View Article : Google Scholar
14	Yao J, Qian CJ, Ye B, Zhang X and Liang Y: ERK inhibition enhances TSA-induced gastric cancer cell apoptosis via NF-κB-dependent and Notch-independent mechanism. Life Sci. 91:186–193. 2012. View Article : Google Scholar : PubMed/NCBI
15	Tai DI, Tsai SL, Chang YH, Huang SN, Chen TC, Chang KS and Liaw YF: Constitutive activation of nuclear factor kappaB in hepatocellular carcinoma. Cancer. 89:2274–2281. 2000. View Article : Google Scholar : PubMed/NCBI
16	Li W, Tan D, Zenali MJ and Brown RE: Constitutive activation of nuclear factor-kappa B (NF-κB) signaling pathway in fibrolamellar hepatocellular carcinoma. Int J Clin Exp Patho. 3:238–243. 2010.
17	Wang WH, Chiang IT, Liu YC, Hsu FT, Chen HW, Chen CL, Lee YJ, Lin WJ and Hwang JJ: Simultaneous imaging of temporal changes of NF-κB activity and viable tumor cells in Huh7/NF-kappaB-tk-luc2/rfp tumor-bearing mice. In Vivo. 27:339–350. 2013.PubMed/NCBI
18	Pan CC, Kavanagh BD, Dawson LA, LI XA, Das SK, Miften M and Tan RK: Radiation-associated liver injury. Int J Radiat Oncol. 76 Suppl:S94–S100. 2010. View Article : Google Scholar
19	Liu YC, Chiang IT, Hsu FT and Hwang JJ: Using NF-κB as a molecular target for theranostics in radiation oncology research. Expert Rev Mol Diagn. 12:139–146. 2012. View Article : Google Scholar : PubMed/NCBI
20	Dai Y, Guzman ML, Chen S, Wang L, Yeung SK, Pei XY, Dent P, Jordan CT and Grant S: The NF (Nuclear factor)-kappaB inhibitor parthenolide interacts with histone deacetylase inhibitors to induce MKK7/JNK1-dependent apoptosis in human acute myeloid leukaemia cells. Brit J Haematol. 151:70–83. 2010. View Article : Google Scholar
21	Hsu FT, Liu YC, Chiang IT, Liu RS, Wang HE, Lin WJ and Hwang JJ: Sorafenib increases efficacy of vorinostat against human hepatocellular carcinoma through transduction inhibition of vorinostat-induced ERK/NF-κB signaling. Int J Oncol. 45:177–188. 2014. View Article : Google Scholar : PubMed/NCBI
22	Chiang IT, Liu YC, Wang WH, Hsu FT, Chen HW, Lin WJ, Chang WY and Hwang JJ: Sorafenib inhibits TPA-induced MMP-9 and VEGF expression via suppression of ERK/NF-κB pathway in hepatocellular carcinoma cells. In Vivo. 26:671–681. 2012.PubMed/NCBI
23	Kuo YC, Lin WC, Chiang IT, Chang YF, Chen CW, Su SH, Chen CL and Hwang JJ: Sorafenib sensitizes human colorectal carcinoma to radiation via suppression of NF-κB expression in vitro and in vivo. Biomed Pharmacother. 66:12–20. 2012. View Article : Google Scholar : PubMed/NCBI
24	Meidhof S, Brabletz S, Lehmann W, Preca BT, Mock K, Ruh M, Schüler J, Berthold M, Weber A, Burk U, et al: ZEB-1 associated drug resistance in cancer cells is reversed by class I HDAC inhibitor mocetinostat. EMBO Mol Med. 7:831–847. 2015. View Article : Google Scholar : PubMed/NCBI
25	Rundall BK, Denlinger CE and Jones DR: Combined histone deacetylase and NF-kappaB inhibition sensitizes non-small cell lung cancer to cell death. Surgery. 136:416–425. 2004. View Article : Google Scholar : PubMed/NCBI
26	Domingo-Domenech J, Pippa R, Tapia M, Gascon P, Bachs O and Bosch M: Inactivation of NF-kappaB by proteasome inhibition contributes to increased apoptosis induced by histone deacetylase inhibitors in human breast cancer cells. Breast Cancer Res Tr. 112:53–62. 2008. View Article : Google Scholar
27	Ly JD, Grubb DR and Lawen A: The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis. 8:115–128. 2003. View Article : Google Scholar : PubMed/NCBI
28	Li Q, Hu Y, Xi M, He L, Zhao L and Liu M: Sorafenib modulates the radiosensitivity of hepatocellular carcinoma cells in vitro in a schedule-dependent manner. BMC Cancer. 12:4852012. View Article : Google Scholar : PubMed/NCBI
29	Yu W, Gu K, Yu Z, Yuan D, He M, Ma N, Lai S, Zhao J, Ren Z, Zhang X, et al: Sorafenib potentiates irradiation effect in hepatocellular carcinoma in vitro and in vivo. Cancer Lett. 329:109–117. 2013. View Article : Google Scholar : PubMed/NCBI
30	Chen J CH, Chuang HY, Hsu FT, Chen YC, Chien YC and Hwang JJ: Sorafenib pretreatment enhances radiotherapy through targeting MEK/ERK/NF-κB pathway in human hepatocellular carcinoma-bearing mouse model. Oncotarget. 2016.(in press).
31	Komarova NL, Katouli AA and Wodarz D: Combination of two but not three current targeted drugs can improve therapy of chronic myeloid leukemia. PLoS One. 4:e44232019. View Article : Google Scholar