Combination of SNX-2112 with 5-FU exhibits antagonistic effect in esophageal cancer cells

Liu,Yuting; Wang,Xiao; Wang,Ying; Zhang,Yi; Zheng,Kai; Yan,Haizhao; Zhang,Li; Chen,Wenbo; Wang,Xiaoyan; Liu,Qiuying; Wang,Shaoxiang; Wang,Yifei

doi:10.3892/ijo.2014.2714

Combination of SNX-2112 with 5-FU exhibits antagonistic effect in esophageal cancer cells

Authors:
- Yuting Liu
- Xiao Wang
- Ying Wang
- Yi Zhang
- Kai Zheng
- Haizhao Yan
- Li Zhang
- Wenbo Chen
- Xiaoyan Wang
- Qiuying Liu
- Shaoxiang Wang
- Yifei Wang
View Affiliations

Affiliations: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, P.R. China, Department of Biotechnology, Jinan University, Guangzhou 510632, P.R. China, School of Medicine, Shenzhen University, Shenzhen 518060, P.R. China
Published online on: October 20, 2014 https://doi.org/10.3892/ijo.2014.2714
Pages: 299-307

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

The low efficacy of single-drug chemotherapy forms the basis for combination therapy in esophageal squamous cell carcinoma. SNX-2112, a selective heat shock protein 90 (Hsp90) inhibitor, was recently reported as being effective in combination with cisplatin and paclitaxel. In this study, we investigated the effect of SNX-2112 in combination with 5-fluorouracil (5-FU), another first-line anticancer drug, in esophageal cancer. Unexpectedly, tetrazolium assay revealed that the combination of SNX-2112 with 5-FU exhibited antagonistic effect. Flow cytometry revealed that the SNX-2112 and 5-FU combination greatly decreased the number of G2/M cells compared to SNX-2112-only treatment in Eca‑109 cells. This effect might be related to the altered mRNA level of cyclin-related genes including cyclin D1, Chk2 and Cdk4. Further, 5-FU attenuated SNX-2112-induced apoptosis by decreasing poly(ADP-ribose) polymerase (PARP) cleavage and inactivating caspase-3, -8 and -9. Additionally, 5-FU suppressed the SNX-2112-induced decrease of mitochondrial membrane potential. Moreover, 5-FU partly recovered Hsp90 client proteins, including Akt, p-Akt, inhibitor of κB kinase (IKK)α, extracellular signal-regulated kinase (ERK)1/2, and glycogen synthase kinase (GSK)-3β, which SNX-2112 had downregulated. Taken together, this is the first report that the combination of SNX-2112 with 5-FU exhibited antagonistic effect in esophageal cancer cells by affecting growth inhibition, cell cycle, apoptosis, and Hsp90 client proteins, suggesting that care is required in the clinical application of combined SNX-2112 and 5-FU.

View Figures

View References

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2	He YT, Hou J, Chen ZF, et al: Trends in incidence of esophageal and gastric cardia cancer in high-risk areas in China. Eur J Cancer Prev. 17:71–76. 2008. View Article : Google Scholar : PubMed/NCBI
3	Tew WP, Kelsen DP and Ilson DH: Targeted therapies for esophageal cancer. Oncologist. 10:590–601. 2005. View Article : Google Scholar : PubMed/NCBI
4	Khushalani NI, Leichman CG, Proulx G, et al: Oxaliplatin in combination with protracted-infusion fluorouracil and radiation: report of a clinical trial for patients with esophageal cancer. J Clin Oncol. 20:2844–2850. 2002. View Article : Google Scholar : PubMed/NCBI
5	Burmeister BH, Walpole ET, D’Arcy N, et al: A phase II trial of chemoradiation therapy with weekly oxaliplatin and protracted infusion of 5-fluorouracil for esophageal cancer. Invest New Drugs. 27:275–279. 2009. View Article : Google Scholar : PubMed/NCBI
6	Juergens RA and Forastiere A: Combined modality therapy of esophageal cancer. J Natl Compr Cancer Netw. 6:851–861. 2008.PubMed/NCBI
7	Neckers L: Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med. 8(Suppl 4): S55–S61. 2002. View Article : Google Scholar : PubMed/NCBI
8	Faried A, Sohda M, Nakajima M, Miyazaki T, Kato H and Kuwano H: Expression of heat-shock protein Hsp60 correlated with the apoptotic index and patient prognosis in human oesophageal squamous cell carcinoma. Eur J Cancer. 40:2804–2811. 2004. View Article : Google Scholar : PubMed/NCBI
9	Liu KS, Zhang Y, Ding WC, et al: The selective Hsp90 inhibitor BJ-B11 exhibits potent antitumor activity via induction of cell cycle arrest, apoptosis and autophagy in Eca-109 human esophageal squamous carcinoma cells. Int J Oncol. 41:2276–2284. 2012.
10	Liu XL, Xiao B, Yu ZC, et al: Down-regulation of Hsp90 could change cell cycle distribution and increase drug sensitivity of tumor cells. World J Gastroenterol. 5:199–208. 1999.PubMed/NCBI
11	Wu X, Wanders A, Wardega P, et al: Hsp90 is expressed and represents a therapeutic target in human oesophageal cancer using the inhibitor 17-allylamino-17-demethoxygeldanamycin. Br J Cancer. 100:334–343. 2009. View Article : Google Scholar : PubMed/NCBI
12	Bao XH, Takaoka M, Hao H-F, et al: Antiproliferative effect of the HSP90 inhibitor NVP-AUY922 is determined by the expression of PTEN in esophageal cancer. Oncol Rep. 29:45–50. 2013.PubMed/NCBI
13	Rajan A, Kelly RJ, Trepel JB, et al: A phase I study of PF-04929113 (SNX-5422), an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumor malignancies and lymphomas. Clin Cancer Res. 17:6831–6839. 2011. View Article : Google Scholar : PubMed/NCBI
14	Wang X, Wang S, Liu Y, et al: The Hsp90 inhibitor SNX-2112 induces apoptosis of human hepatocellular carcinoma cells: the role of ER stress. Biochem Biophys Res Commun. 446:160–166. 2014. View Article : Google Scholar : PubMed/NCBI
15	Wang R, Shao F, Liu Z, et al: The Hsp90 inhibitor SNX-2112, induces apoptosis in multidrug resistant K562/ADR cells through suppression of Akt/NF-kappaB and disruption of mitochondria-dependent pathways. Chem Biol Interact. 205:1–10. 2013. View Article : Google Scholar : PubMed/NCBI
16	Wang SX, Ju HQ, Liu KS, et al: SNX-2112, a novel Hsp90 inhibitor, induces G2/M cell cycle arrest and apoptosis in MCF-7 cells. Biosci Biotechnol Biochem. 75:1540–1545. 2011. View Article : Google Scholar : PubMed/NCBI
17	Friedman JA, Wise SC, Hu M, et al: HSP90 inhibitor SNX5422/2112 targets the dysregulated signal and transcription factor network and malignant phenotype of head and neck squamous cell carcinoma. Transl Oncol. 6:429–441. 2013. View Article : Google Scholar : PubMed/NCBI
18	Liu KS, Liu H, Qi JH, et al: SNX-2112, an Hsp90 inhibitor, induces apoptosis and autophagy via degradation of Hsp90 client proteins in human melanoma A-375 cells. Cancer Lett. 318:180–188. 2012. View Article : Google Scholar : PubMed/NCBI
19	Chou T-C and Talalay P: Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 22:27–55. 1984. View Article : Google Scholar : PubMed/NCBI
20	Chou T-C: Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 70:440–446. 2010. View Article : Google Scholar : PubMed/NCBI
21	Kroemer G, Galluzzi L and Brenner C: Mitochondrial membrane permeabilization in cell death. Physiol Rev. 87:99–163. 2007. View Article : Google Scholar : PubMed/NCBI
22	Ohba S, Hirose Y, Yoshida K, Yazaki T and Kawase T: Inhibition of 90-kD heat shock protein potentiates the cytotoxicity of chemotherapeutic agents in human glioma cells. J Neurosurg. 112:33–42. 2010. View Article : Google Scholar : PubMed/NCBI
23	Proia DA, Sang J, He S, et al: Synergistic activity of the Hsp90 inhibitor ganetespib with taxanes in non-small cell lung cancer models. Invest New Drugs. 30:2201–2209. 2012. View Article : Google Scholar : PubMed/NCBI
24	Casimiro MC, Crosariol M, Loro E, Li Z and Pestell RG: Cyclins and cell cycle control in cancer and disease. Genes Cancer. 3:649–657. 2012. View Article : Google Scholar : PubMed/NCBI
25	Stepanova L, Leng X, Parker SB and Harper JW: Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. Genes Dev. 10:1491–1502. 1996. View Article : Google Scholar : PubMed/NCBI
26	El-Awady RA, Saleh EM, Ezz M and Elsayed AM: Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells. Toxicol Appl Pharmacol. 255:271–286. 2011. View Article : Google Scholar : PubMed/NCBI
27	Crow MT, Mani K, Nam Y-J and Kitsis RN: The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res. 95:957–970. 2004. View Article : Google Scholar : PubMed/NCBI
28	Okawa Y, Hideshima T, Steed P, et al: SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK. Blood. 113:846–855. 2009. View Article : Google Scholar : PubMed/NCBI
29	Fukuyama R, Ng KP, Cicek M, et al: Role of IKK and oscillatory NFkappaB kinetics in MMP-9 gene expression and chemoresistance to 5-fluorouracil in RKO colorectal cancer cells. Mol Carcinog. 46:402–413. 2007. View Article : Google Scholar : PubMed/NCBI
30	Azuma M, Yamashita T, Aota K, Tamatani T and Sato M: 5-Fluorouracil suppression of NF-KappaB is mediated by the inhibition of IKappab kinase activity in human salivary gland cancer cells. Biochem Biophys Res Commun. 282:292–296. 2001. View Article : Google Scholar : PubMed/NCBI