Anticancer activity of SAHA, a potent histone deacetylase inhibitor, in NCI-H460 human large-cell lung carcinoma cells in vitro and in vivo

Zhao,Yanxia; Yu,Dandan; Wu,Hongge; Liu,Hongli; Zhou,Hongxia; Gu,Runxia; Zhang,Ruiguang; Zhang,Sheng; Wu,Gang

doi:10.3892/ijo.2013.2193

Anticancer activity of SAHA, a potent histone deacetylase inhibitor, in NCI-H460 human large-cell lung carcinoma cells in vitro and in vivo

Authors:
- Yanxia Zhao
- Dandan Yu
- Hongge Wu
- Hongli Liu
- Hongxia Zhou
- Runxia Gu
- Ruiguang Zhang
- Sheng Zhang
- Gang Wu
View Affiliations

Affiliations: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P.R. China
Published online on: November 28, 2013 https://doi.org/10.3892/ijo.2013.2193
Pages: 451-458

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

Suberoylanilide hydroxamic acid (SAHA), a potent pan-histone deacetylase (HDAC) inhibitor, has been clinically approved for the treatment of cutaneous T-cell lymphoma (CTCL). SAHA has also been shown to exert a variety of anticancer activities in many other types of tumors, however, few studies have been reported in large-cell lung carcinoma (LCC). Our study aimed to investigate the potential antitumor effects of SAHA on LCC cells. Here, we report that SAHA was able to inhibit the proliferation of the LCC cell line NCI-H460 in a dose- and time-dependent manner, induced cell apoptosis and G2/M cell cycle arrest, decreased AKT and ERK phosphorylation, inhibited the expression of pro-angiogenic factors (VEGF, HIF-1α) in vitro, and suppressed tumor progression in an NCI-H460 cell nude mouse xenograft model in vivo. These results indicate that SAHA can exert its strong antitumor effects in LCC patient.

View Figures

View References

1.	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar
2.	Brambilla E: [Classification of broncho-pulmonary cancers (WHO 1999)]. Rev Mal Respir. 19:455–466. 2002.(In French).
3.	Varlotto JM, Medford-Davis LN, Recht A, et al: Should large cell neuroendocrine lung carcinoma be classified and treated as a small cell lung cancer or with other large cell carcinomas? J Thorac Oncol. 6:1050–1058. 2011. View Article : Google Scholar : PubMed/NCBI
4.	Sun JM, Ahn MJ, Ahn JS, et al: Chemotherapy for pulmonary large cell neuroendocrine carcinoma: similar to that for small cell lung cancer or non-small cell lung cancer? Lung Cancer. 77:365–370. 2012. View Article : Google Scholar : PubMed/NCBI
5.	Swarts DRA, Ramaekers FCS and Speel E-JM: Molecular and cellular biology of neuroendocrine lung tumors: evidence for separate biological entities. Biochim Biophys Acta. 1826:255–271. 2012.PubMed/NCBI
6.	Duvic M, Talpur R, Ni X, et al: Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood. 109:31–39. 2007. View Article : Google Scholar : PubMed/NCBI
7.	Olsen EA, Kim YH, Kuzel TM, et al: Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol. 25:3109–3115. 2007. View Article : Google Scholar : PubMed/NCBI
8.	Marchion D and Munster P: Development of histone deacetylase inhibitors for cancer treatment. Expert Rev Anticancer Ther. 7:583–598. 2007. View Article : Google Scholar : PubMed/NCBI
9.	Fiskus W, Hembruff SL, Rao R, et al: Co-treatment with vorinostat synergistically enhances activity of Aurora kinase inhibitor against human breast cancer cells. Breast Cancer Res Treat. 135:433–444. 2012. View Article : Google Scholar
10.	Lautz TB, Jie C, Clark S, et al: The effect of vorinostat on the development of resistance to doxorubicin in neuroblastoma. PLoS One. 7:e408162012. View Article : Google Scholar : PubMed/NCBI
11.	Muscal JA, Scorsone KA, Zhang L, Ecsedy JA and Berg SL: Additive effects of vorinostat and MLN8237 in pediatric leukemia, medulloblastoma, and neuroblastoma cell lines. Invest New Drugs. 31:39–45. 2013. View Article : Google Scholar : PubMed/NCBI
12.	Karelia N, Desai D, Hengst JA, Amin S, Rudrabhatla SV and Yun J: Selenium-containing analogs of SAHA induce cytotoxicity in lung cancer cells. Bioorg Med Chem Lett. 20:6816–6819. 2010. View Article : Google Scholar : PubMed/NCBI
13.	Witta S: Histone deacetylase inhibitors in non-small-cell lung cancer. J Thorac Oncol. 7:S404–S406. 2012. View Article : Google Scholar : PubMed/NCBI
14.	Kovacic P and Edwards CL: Hydroxamic acids (therapeutics and mechanism): chemistry, acyl nitroso, nitroxyl, reactive oxygen species, and cell signaling. J Recept Signal Transduct Res. 31:10–19. 2011. View Article : Google Scholar : PubMed/NCBI
15.	Osada H: ASH1 gene is a specific therapeutic target for lung cancers with neuroendocrine features. Cancer Res. 65:10680–10685. 2005. View Article : Google Scholar : PubMed/NCBI
16.	Lee M, Draoui M, Zia F, et al: Epidermal growth factor receptor monoclonal antibodies inhibit the growth of lung cancer cell lines. J Natl Cancer Inst Monogr. 117–123. 1992.PubMed/NCBI
17.	Backs J and Olson EN: Control of cardiac growth by histone acetylation/deacetylation. Circ Res. 98:15–24. 2006. View Article : Google Scholar : PubMed/NCBI
18.	Rangwala S, Zhang C and Duvic M: HDAC inhibitors for the treatment of cutaneous T-cell lymphomas. Future Med Chem. 4:471–486. 2012. View Article : Google Scholar : PubMed/NCBI
19.	Marks PA: Discovery and development of SAHA as an anticancer agent. Oncogene. 26:1351–1356. 2007. View Article : Google Scholar : PubMed/NCBI
20.	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
21.	Khan O and La Thangue NB: HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol Cell Biol. 90:85–94. 2012. View Article : Google Scholar : PubMed/NCBI
22.	Fernandez FG and Battafarano RJ: Large-cell neuroendocrine carcinoma of the lung. Cancer Control. 13:270–275. 2006.PubMed/NCBI
23.	Gollard R, Jhatakia S, Elliott M and Kosty M: Large cell/neuroendocrine carcinoma. Lung Cancer. 69:13–18. 2010. View Article : Google Scholar : PubMed/NCBI
24.	Worster DT, Schmelzle T, Solimini NL, et al: Akt and ERK control the proliferative response of mammary epithelial cells to the growth factors IGF-1 and EGF through the cell cycle inhibitor p57^Kip2. Sci Signal. 5:ra192012. View Article : Google Scholar : PubMed/NCBI
25.	Shaw RJ and Cantley LC: Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 441:424–430. 2006. View Article : Google Scholar : PubMed/NCBI
26.	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
27.	Engelman JA: Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 9:550–562. 2009. View Article : Google Scholar : PubMed/NCBI
28.	Roberts PJ and Der CJ: Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 26:3291–3310. 2007. View Article : Google Scholar : PubMed/NCBI
29.	Cagnol S and Chambard JC: ERK and cell death: mechanisms of ERK-induced cell death - apoptosis, autophagy and senescence. FEBS J. 277:2–21. 2010. View Article : Google Scholar : PubMed/NCBI
30.	Hanahan D and Folkman J: Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 86:353–364. 1996. View Article : Google Scholar : PubMed/NCBI
31.	Carmeliet P, Dor Y, Herbert JM, et al: Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 394:485–490. 1998. View Article : Google Scholar : PubMed/NCBI
32.	Semenza GL: Evaluation of HIF-1 inhibitors as anticancer agents. Drug Discov Today. 12:853–859. 2007. View Article : Google Scholar : PubMed/NCBI
33.	Semenza GL: Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 3:721–732. 2003. View Article : Google Scholar
34.	Muhlethaler-Mottet A, Meier R, Flahaut M, et al: Complex molecular mechanisms cooperate to mediate histone deacetylase inhibitors anti-tumour activity in neuroblastoma cells. Mol Cancer. 7:552008. View Article : Google Scholar
35.	Shankar S, Davis R, Singh KP, Kurzrock R, Ross DD and Srivastava RK: Suberoylanilide hydroxamic acid (Zolinza/ vorinostat) sensitizes TRAIL-resistant breast cancer cells orthotopically implanted in BALB/c nude mice. Mol Cancer Ther. 8:1596–1605. 2009. View Article : Google Scholar