VX680 suppresses the growth of HepG2 cells and enhances the chemosensitivity to cisplatin

Yao,Rucheng; Zheng,Jun; Zheng,Weihong; Gong,Yuan; Liu,Wei; Xing,Rongchun

doi:10.3892/ol.2013.1648

VX680 suppresses the growth of HepG2 cells and enhances the chemosensitivity to cisplatin

Authors:
- Rucheng Yao
- Jun Zheng
- Weihong Zheng
- Yuan Gong
- Wei Liu
- Rongchun Xing
View Affiliations

Affiliations: Department of General Surgery, The First College of Clinical Medical Sciences, Three Gorges University, Yichang, Hubei 443003, P.R. China, Department of Pharmacology, Medical Science College, Three Gorges University, Yichang, Hubei 443003, P.R. China, Department of Respiratory Medicine, The First College of Clinical Medical Sciences, Three Gorges University, Yichang, Hubei 443003, P.R. China
Published online on: October 29, 2013 https://doi.org/10.3892/ol.2013.1648
Pages: 121-124

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

VX680 is an Aurora A inhibitor. It has been reported to inhibit the growth of the HepG2 cell line in several studies. However, whether it enhances chemosensitivity to cisplatin remains unclear. In this study, the synergistic effect of VX680 and cisplatin on the proliferation of HepG2 cells was determined by MTT assay. The changes in cell apoptosis were detected by flow cytometry. Aurora A, Bcl‑2 and p53 protein levels were analyzed by western blotting. This study demonstrated that VX680, cisplatin and a combination of the two inhibit the growth of HepG2 cells in a dose‑ and time‑dependent manner. A synergistic effect was observed with the combined therapy. Moreover, the inhibitory effect of VX680 was positively correlated with the expression of Aurora A. The rate of apoptosis in the combined group was significantly higher compared with that of the VX680 and cisplatin groups. In addition, VX680 and cisplatin increased the expression of the p53 protein. Cisplatin reduced the expression of Bcl‑2 protein, while VX680 did not. In the combined group, the expression of Bcl‑2 and p53 changed significantly compared with the single drug group and control group. This study suggests that Aurora A may represent a valid target in hepatocellular carcinoma. We also demonstrated that the Aurora A inhibitor VX680 has a synergistic effect with cisplatin.

View Figures

View References

1	Nathan H, Segev DL, Mayo SC, Choti MA, Cameron AM, Wolfgang CL, Hirose K, Edil BH, Schulick RD and Pawlik TM: National trends in surgical procedures for hepatocellular carcinoma: 1998–2008. Cancer. 118:1838–1844. 2012.
2	Carmena M and Earnshaw WC: The cellular geography of aurora kinases. Nat Rev Mol Cell Biol. 4:842–854. 2003. View Article : Google Scholar : PubMed/NCBI
3	Zhang XH, Rao M, Loprieato JA, et al: Aurora A, Aurora B and survivin are novel targets of transcriptional regulation by histone deacetylase inhibitors in non-small cell lung cancer. Cancer Biol Ther. 7:1388–1397. 2008. View Article : Google Scholar
4	Lam AK, Ong K and Ho YH: Aurora kinase expression in colorectal adenocarcinoma: correlations with clinicopathological features, p16 expression, and telomerase activity. Hum Pathol. 39:599–604. 2008. View Article : Google Scholar
5	Lee EC, Frolov A, Li R, Ayala G and Greenberg NM: Targeting Aurora kinases for the treatment of prostate cancer. Cancer Res. 66:4996–5002. 2006. View Article : Google Scholar : PubMed/NCBI
6	Terakawa T, Miyake H, Kumano M and Fujisawa M: Growth inhibition and enhanced chemosensitivity induced by down-regulation of Aurora-A in human renal cell carcinoma Caki-2 cells using short hairpin RNA. Oncol Lett. 2:713–717. 2011.
7	Tanaka S, Arii S, Yasen M, Mogushi K, Su NT, Zhao C, Imoto I, Eishi Y, Inazawa J, Miki Y and Tanaka H: Aurora kinase B is a predictive factor for the aggressive recurrence of hepatocellular carcinoma after curative hepatectomy. Br J Surg. 95:611–619. 2008. View Article : Google Scholar
8	Kuang Y, Cai J, Li D, Han Q, Cao J and Wang Z: Repression of Dicer is associated with invasive phenotype and chemoresistance in ovarian cancer. Oncol Lett. 5:1149–1154. 2013.PubMed/NCBI
9	Park HS, Park WS, Bondaruk J, et al: Quantitation of Aurora kinase A gene copy number in urine sediments and bladder cancer detection. J Natl Cancer Inst. 100:1401–1411. 2008. View Article : Google Scholar : PubMed/NCBI
10	Wang XX, Liu R, Jin SQ, Fan FY and Zhan QM: Overexpression of Aurora-A kinase promotes tumor cell proliferation and inhibits apoptosis in esophageal squamous cell carcinoma cell line. Cell Res. 16:356–366. 2006. View Article : Google Scholar : PubMed/NCBI
11	Qi W, Cooke LS, Liu X, Rimsza L, Roe DJ, Manziolli A, Persky DO, Miller TP and Mahadevan D: Aurora inhibitor MLN8237 in combination with docetaxel enhances apoptosis and anti-tumor activity in mantle cell lymphoma. Biochem Pharmacol. 81:881–890. 2011. View Article : Google Scholar : PubMed/NCBI
12	Shimomura T, Hasako S, Nakatsuru Y, et al: MK-5108, a highly selective Aurora-A kinase inhibitor, shows antitumor activity alone and in combination with docetaxel. Mol Cancer Ther. 9:157–166. 2010. View Article : Google Scholar
13	Harrington EA, Bebbington D, Moore J, et al: VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med. 10:262–267. 2004. View Article : Google Scholar : PubMed/NCBI
14	Fiskus W, Wang Y, Joshi R, et al: Cotreatment with vorinostat enhances activity of MK-0457 (VX-680) against acute and chronic myelogenous leukemia cells. Clin Cancer Res. 14:6106–6115. 2008. View Article : Google Scholar : PubMed/NCBI
15	Jin ZJ: Addition in drug combination. Zhongguo Yao Li Xue Bao. 1:70–76. 1980.(In Chinese).
16	Jeng YM, Peng SY, Lin CY and Hsu HC: Overexpression and amplification of Aurora-A in hepatocellular carcinoma. Clin Cancer Res. 10:2065–2071. 2004. View Article : Google Scholar : PubMed/NCBI
17	Lin ZZ, Jeng YM, Hu FC, Pan HW, Tsao HW, Lai PL, Lee PH, Cheng AL and Hsu HC: Significance of Aurora B overexpression in hepatocellular carcinoma. Aurora B Overexpression in HCC. BMC Cancer. 10:4612010. View Article : Google Scholar : PubMed/NCBI
18	Lin ZZ, Hsu HC, Hsu CH, et al: The Aurora kinase inhibitor VE-465 has anticancer effects in pre-clinical studies of human hepatocellular carcinoma. J Hepatol. 50:518–527. 2009. View Article : Google Scholar : PubMed/NCBI
19	Yu Y, Zhang Y, Hu J, et al: MARVELD1 inhibited cell proliferation and enhance chemosensitivity via increasing expression of p53 and p16 in hepatocellular carcinoma. Cancer Sci. 103:716–722. 2012. View Article : Google Scholar : PubMed/NCBI
20	Katayama H, Sasai K, Kawai H, Yuan ZM, Bondaruk J, Suzuki F, Fujii S, Arlinghaus RB, Czerniak BA and Sen S: Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nat Genet. 36:55–62. 2004. View Article : Google Scholar : PubMed/NCBI