Suberoylanilide hydroxamic acid enhances the antitumor activity of oxaliplatin by reversing the oxaliplatin‑induced Src activation in gastric cancer cells

Zhou,Chenfei; Ji,Jun; Shi,Min; Yang,Liu; Yu,Yingyan; Liu,Bingya; Zhu,Zhenggang; Zhang,Jun

doi:10.3892/mmr.2014.2548

Suberoylanilide hydroxamic acid enhances the antitumor activity of oxaliplatin by reversing the oxaliplatin‑induced Src activation in gastric cancer cells

Authors:
- Chenfei Zhou
- Jun Ji
- Min Shi
- Liu Yang
- Yingyan Yu
- Bingya Liu
- Zhenggang Zhu
- Jun Zhang
View Affiliations

Affiliations: Department of Surgery, Shanghai Institute of Digestive Surgery, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China
Published online on: September 9, 2014 https://doi.org/10.3892/mmr.2014.2548
Pages: 2729-2735

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

Oxaliplatin and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA), also known as vorinostat, are potent antitumor agents. The aim of this study was to investigate the effect of SAHA on the antitumor efficacy of oxaliplatin in gastric cancer and the interaction between oxaliplatin and SAHA. Cell growth inhibition was evaluated using Cell Counting Kit‑8 and colony formation assays. Xenografts established in nude mice were used to assess tumor growth in vivo. Western blot analysis was used to detect the expression of acetyl‑histone H3, phosphorylated histone H2AX (γH2AX), B‑cell lymphoma 2 (Bcl‑2), cleaved caspase‑3, cleaved poly (ADP‑ribose) polymerase (PARP), phosphorylated- (p-)Src, Src, Akt and p‑Akt in gastric cancer cells. The in vitro growth of SGC‑7901, Hs746T and MKN28 gastric cancer cells was found to be dose‑dependently inhibited by oxaliplatin and SAHA. Furthermore, combined treatment was observed to be more effective in inhibiting cancer cell growth and colony formation than monotherapy. Similar effects were found in the xenografts. A positive interaction was identified between oxaliplatin and SAHA (between‑subject effects of oxaliplatin and SAHA, P<0.001). In addition, combined exposure to oxaliplatin and SAHA increased γH2AX expression and decreased Bcl‑2 expression. The expression of cleaved caspase‑3 and PARP was also increased with combination treatment. Oxaliplatin‑induced Src phosphorylation was detected in gastric cancer cells, as we have previously reported. However, this effect was inhibited by SAHA. The oxaliplatin‑induced Src phosphorylation was not impaired with Akt inhibition. In conclusion, oxaliplatin and SAHA exhibited a positive interaction when used in combination and were found to suppress gastric cancer cell survival and growth. The reversal of oxaliplatin‑induced Src activation may be responsible for this positive interaction.

View Figures

View References

1	Zhao P, Dai M, Chen W and Li N: Cancer trends in China. Jpn J Clin Oncol. 40:281–285. 2010. View Article : Google Scholar
2	Hartgrink HH, Jansen EP, van Grieken NC and van de Velde CJ: Gastric cancer. Lancet. 374:477–490. 2009. View Article : Google Scholar
3	Cervantes A, Roda D, Tarazona N, et al: Current questions for the treatment of advanced gastric cancer. Cancer Treat Rev. 39:60–67. 2013. View Article : Google Scholar : PubMed/NCBI
4	Bang YJ, Van Cutsem E, Feyereislova A, et al: ToGA Trial Investigators: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 376:687–697. 2010. View Article : Google Scholar
5	Ohtsu A, Shah MA, Van Cutsem E, et al: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 29:3968–3976. 2011. View Article : Google Scholar
6	Lordick F, Kang YK, Chung HC, et al: Arbeitsgemeinschaft Internistische Onkologie and EXPAND Investigators: Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 14:490–499. 2013. View Article : Google Scholar
7	Waddell T, Chau I, Cunningham D, et al: Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol. 14:481–489. 2013. View Article : Google Scholar
8	Cunningham D, Starling N, Rao S, et al: Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom: Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 358:36–46. 2008. View Article : Google Scholar
9	Rabik CA and Dolan ME: Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev. 33:9–23. 2007. View Article : Google Scholar : PubMed/NCBI
10	Bang YJ, Kim YW, Yang HK, et al: CLASSIC trial investigators; Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 379:315–321. 2012. View Article : Google Scholar
11	Shi M, Lou B, Ji J, et al: Synergistic antitumor effects of dasatinib and oxaliplatin in gastric cancer cells. Cancer Chemother Pharmacol. 72:35–44. 2013. View Article : Google Scholar : PubMed/NCBI
12	Weichert W, Röske A, Gekeler V, et al: Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: a retrospective analysis. Lancet Oncol. 9:139–148. 2008. View Article : Google Scholar
13	Barneda-Zahonero B and Parra M: Histone deacetylases and cancer. Mol Oncol. 6:579–589. 2012. View Article : Google Scholar
14	Mann BS, Johnson JR, Cohen MH, et al: FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist. 12:1247–1252. 2007. View Article : Google Scholar : PubMed/NCBI
15	Carew JS, Giles FJ and Nawrocki ST: Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer Lett. 269:7–17. 2008. View Article : Google Scholar : PubMed/NCBI
16	Yoo C, Ryu MH, Na YS, et al: Phase I and pharmacodynamic study of vorinostat combined with capecitabine and cisplatin as first-line chemotherapy in advanced gastric cancer. Invest New Drugs. 32:271–278. 2014. View Article : Google Scholar : PubMed/NCBI
17	Raymond E, Faivre S, Chaney S, et al: Cellular and molecular pharmacology of oxaliplatin. Mol Cancer Ther. 1:227–235. 2002.
18	Petruccelli LA, Dupéré-Richer D, Pettersson F, et al: Vorinostat induces reactive oxygen species and DNA damage in acute myeloid leukemia cells. PLoS One. 6:e209872011. View Article : Google Scholar : PubMed/NCBI
19	Zhang C, Richon V, Ni X, et al: Selective induction of apoptosis by histone deacetylase inhibitor SAHA in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action. J Invest Dermatol. 125:1045–1052. 2005. View Article : Google Scholar : PubMed/NCBI
20	Chen CS, Weng SC, Tseng PH, et al: Histone acetylation-independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase 1 complexes. J Biol Chem. 280:38879–38887. 2005. View Article : Google Scholar : PubMed/NCBI
21	Bolden JE, Peart MJ and Johnstone RW: Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 5:769–784. 2006. View Article : Google Scholar : PubMed/NCBI
22	Claerhout S, Lim JY, Choi W, et al: Gene expression signature analysis identifies vorinostat as a candidate therapy for gastric cancer. PLoS One. 6:e246622011. View Article : Google Scholar
23	Diyabalanage HV, Granda ML and Hooker JM: Combination therapy: histone deacetylase inhibitors and platinum-based chemotherapeutics for cancer. Cancer Lett. 329:1–8. 2013. View Article : Google Scholar : PubMed/NCBI
24	Rikiishi H, Shinohara F, Sato T, et al: Chemosensitization of oral squamous cell carcinoma cells to cisplatin by histone deacetylase inhibitor, suberoylanilide hydroxamic acid. Int J Oncol. 30:1181–1188. 2007.PubMed/NCBI
25	Woynarowski JM, Faivre S, Herzig MC, et al: Oxaliplatin-induced damage of cellular DNA. Mol Pharmacol. 58:920–927. 2000.PubMed/NCBI
26	Faivre S, Chan D, Salinas R, et al: DNA strand breaks and apoptosis induced by oxaliplatin in cancer cells. Biochem Pharmacol. 66:225–237. 2003. View Article : Google Scholar : PubMed/NCBI
27	Conti C, Leo E, Eichler GS, et al: Inhibition of histone deacetylase in cancer cells slows down replication forks, activates dormant origins, and induces DNA damage. Cancer Res. 70:4470–4480. 2010. View Article : Google Scholar : PubMed/NCBI
28	New M, Olzscha H and La Thangue NB: HDAC inhibitor-based therapies: can we interpret the code? Mol Oncol. 6:637–656. 2012. View Article : Google Scholar : PubMed/NCBI
29	Thompson RC, Vardinogiannis I and Gilmore TD: The sensitivity of diffuse large B-cell lymphoma cell lines to histone deacetylase inhibitor-induced apoptosis is modulated by BCL-2 family protein activity. PLoS One. 8:e628222013. View Article : Google Scholar
30	Hirsch CL, Smith-Windsor EL and Bonham K: Src family kinase members have a common response to histone deacetylase inhibitors in human colon cancer cells. Int J Cancer. 118:547–554. 2006. View Article : Google Scholar
31	Jiang T and Qiu Y: Interaction between Src and a C-terminal proline-rich motif of Akt is required for Akt activation. J Biol Chem. 278:15789–15793. 2003. View Article : Google Scholar : PubMed/NCBI
32	Summy JM and Gallick GE: Treatment for advanced tumors: SRC reclaims center stage. Clin Cancer Res. 12:1398–1401. 2006. View Article : Google Scholar : PubMed/NCBI
33	Hsieh AC, Truitt ML and Ruggero D: Oncogenic AKTivation of translation as a therapeutic target. Br J Cancer. 105:329–336. 2011. View Article : Google Scholar : PubMed/NCBI
34	Liu J, Fu XQ, Zhou W, et al: LY294002 potentiates the anti-cancer effect of oxaliplatin for gastric cancer via death receptor pathway. World J Gastroenterol. 17:181–190. 2011. View Article : Google Scholar : PubMed/NCBI