Therapeutic potential of sepantronium bromide YM155 in gemcitabine-resistant human urothelial carcinoma cells

Huang,Yen Ta; Cheng,Chuan Chu; Lin,Tzu Chun; Chiu,Ted H.; Lai,Pei Chun

doi:10.3892/or.2013.2882

Therapeutic potential of sepantronium bromide YM155 in gemcitabine-resistant human urothelial carcinoma cells

Authors:
- Yen Ta Huang
- Chuan Chu Cheng
- Tzu Chun Lin
- Ted H. Chiu
- Pei Chun Lai
View Affiliations

Affiliations: Department of Pharmacology, Tzu Chi University, Hualien, Taiwan, R.O.C., Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan, R.O.C., Department of Medicine, Tzu Chi University, Hualien, Taiwan, R.O.C.
Published online on: November 28, 2013 https://doi.org/10.3892/or.2013.2882
Pages: 771-780

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

Survivin is overexpressed in transitional cell carcinoma (TCC), the most common type of bladder cancer. Previous reports demonstrated that knockdown of survivin by siRNA induced apoptosis of TCC cells. The present study evaluated the therapeutic effects of sepantronium bromide (YM155), a novel small molecule survivin inhibitor under clinical trials, on TCC cells in vitro. BFTC905, a grade III TCC cell line derived from a patient of blackfoot disease in Taiwan, was the most gemcitabine-resistant cell line when compared to BFTC909, TSGH8301 and T24 in cytotoxicity assay, resulting from upregulation of securin and bcl-2 after gemcitabine treatment. YM155 caused potent concentration‑dependent cytotoxicity in 4 TCC cell lines (IC50s ≤20 nM), but exhibited no cytotoxicity in survivin-null primary human urothelial cells. For BFTC905 cells, addition of gemcitabine and/or cisplatin, the standard TCC chemotherapy regimen, to YM155 did not exert additive cytotoxic effects. Molecular analyses indicated that YM155 inhibited the proliferation of BFTC905 cells by increasing p27kip1, suppressing Ki-67, and inducing quiescence. In addition, YM155 elicited apoptosis manifested with DNA fragmentation through suppressing the expression of survivin, securin and bcl-2. Furthermore, YM155 induced autophagy in BFTC905 cells as autophagic inhibitor, 3-methyladenine, attenuated YM155-induced LC3B-II levels and reversed the cytotoxicity of YM155. mTOR inhibitors sirolimus and everolimus did not increase YM155-induced expression of LC3B-II nor augment YM155-induced cytotoxicity. These results indicate that YM155 exerts its lethal effect on BFTC905 cells via apoptotic and autophagic death pathways and suggest that YM155 may be a potential drug for the therapy of gemcitabine-resistant bladder cancer.

View Figures

View References

1	Tavora F and Epstein JI: Bladder cancer, pathological classification and staging. BJU Int. 102:1216–1220. 2008. View Article : Google Scholar : PubMed/NCBI
2	Murta-Nascimento C, Schmitz-Dräger, Zeegers MP, et al: Epidemiology of urinary bladder cancer: from tumor development to patient's death. World J Urol. 25:285–295. 2007. View Article : Google Scholar
3	George L, Bladou F, Bardou VJ, et al: Clinical outcome in patients with locally advanced bladder carcinoma treated with conservative multimodality therapy. Urology. 64:488–493. 2004. View Article : Google Scholar : PubMed/NCBI
4	von der Maase H, Hansen SW, Roberts JT, et al: Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 18:3068–3077. 2000.
5	Sternberg CN: Gemcitabine in bladder cancer. Semin Oncol. 27:31–39. 2000.
6	Chaudhary UB, Verma N, Keane T and Gudena V: A phase II study of gemcitabine and irinotecan in patients with locally advanced or metastatic bladder cancer. Am J Clin Oncol. Dec 13–2012.(Epub ahead of print).
7	Culine S, Fléchon A, Guillot A, et al: Gemcitabine or gemcitabine plus oxaliplatin in the first-line treatment of patients with advanced transitional cell carcinoma of the urothelium unfit for cisplatin-based chemotherapy: a randomized phase 2 study of the French Genitourinary Tumor Group (GETUG V01). Eur Urol. 60:1251–1257. 2011.
8	Muramaki M, So A, Hayashi N, et al: Chemosensitization of gemcitabine-resistant human bladder cancer cell line both in vitro and in vivo using antisense oligonucleotide targeting the anti-apoptotic gene, clusterin. BJU Int. 103:384–390. 2009. View Article : Google Scholar
9	Margulis V, Lotan Y and Shariat SF: Survivin: a promising biomarker for detection and prognosis of bladder cancer. World J Urol. 26:59–65. 2008. View Article : Google Scholar : PubMed/NCBI
10	Nakahara T, Takeuchi M, Kinoyama I, et al: YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts. Cancer Res. 67:8014–8021. 2007. View Article : Google Scholar
11	Nakamura N, Yamauchi T, Hiramoto M, et al: Interleukin enhancer-binding factor 3/NF110 is a target of YM155, a suppressant of survivin. Mol Cell Proteomics. 11:M111.013243. 2012. View Article : Google Scholar : PubMed/NCBI
12	Wang Q, Chen Z, Diao X and Huang S: Induction of autophagy-dependent apoptosis by the survivin suppressant YM155 in prostate cancer cells. Cancer Lett. 302:29–36. 2011. View Article : Google Scholar : PubMed/NCBI
13	Nakahara T, Yamanaka K, Hatakeyama S, et al: YM155, a novel survivin suppressant, enhances taxane-induced apoptosis and tumor regression in a human Calu 6 lung cancer xenograft model. Anticancer Drugs. 22:454–462. 2011. View Article : Google Scholar
14	Iwasa T, Okamoto I, Suzuki M, et al: Radiosensitizing effect of YM155, a novel small-molecule survivin suppressant, in non-small cell lung cancer cell lines. Clin Cancer Res. 14:6496–6504. 2008. View Article : Google Scholar : PubMed/NCBI
15	Tzeng CC, Liu HS, Li C, et al: Characterization of two urothelium cancer cell lines derived from a blackfoot disease endemic area in Taiwan. Anticancer Res. 16:1797–1804. 1996.PubMed/NCBI
16	Huang YT, Lai PC, Wu CC, et al: BDNF mediated TrkB activation is a survival signal for transitional cell carcinoma cells. Int J Oncol. 36:1469–1476. 2010.PubMed/NCBI
17	Lai PC, Yang YC, Cheng CC, Chiu TH and Huang YT: Brain-derived neurotrophic factor plus vascular endothelial growth factor additively promotes early growth of the transitional cell carcinoma cell line BFTC905 in vitro and in vivo. Tzu Chi Med J. 25:155–160. 2013. View Article : Google Scholar
18	Chao JI, Su WC and Liu HF: Baicalein induces cancer cell death and proliferation retardation by the inhibition of CDC2 kinase and survivin associated with opposite role of p38 mitogen-activated protein kinase and AKT. Mol Cancer Ther. 6:3039–3048. 2007. View Article : Google Scholar
19	Lai PC, Chen SH, Yang SH, Cheng CC, Chiu TH and Huang YT: Novel survivin inhibitor YM155 elicits cytotoxicity in glioblastoma cell lines with normal or deficiency DNA-dependent protein kinase activity. Pediatr Neonatol. 53:199–204. 2012. View Article : Google Scholar : PubMed/NCBI
20	Liukkonen TJ, Lipponen PK, Helle M and Jauhiainen KE: Immunoreactivity of bcl-2, p53 and EGFr is associated with tumor stage, grade and cell proliferation in superficial bladder cancer. Finnbladder III Group. Urol Res. 25:1–7. 1997. View Article : Google Scholar : PubMed/NCBI
21	Gazzaniga P, Gradilone A, Silvestri I, et al: Variable levels of bcl-2, bcl-X and bax mRNA in bladder cancer progression. Oncol Rep. 5:901–904. 1998.
22	Lai PC, Fang TC, Chiu TH and Huang YT: Overexpression of securin in human transitional cell carcinoma specimens. Tzu Chi Med J. 22:171–176. 2010. View Article : Google Scholar
23	Bommer UA and Thiele BJ: The translationally controlled tumour protein (TCTP). Int J Biochem Cell Biol. 36:379–385. 2004. View Article : Google Scholar
24	Koziol MJ and Gurdon JB: TCTP in development and cancer. Biochem Res Int. 2012:1052032012. View Article : Google Scholar : PubMed/NCBI
25	Lewis KD, Samlowski W, Ward J, et al: A multi-center phase II evaluation of the small molecule survivin suppressor YM155 in patients with unresectable stage III or IV melanoma. Invest New Drugs. 29:161–166. 2011. View Article : Google Scholar : PubMed/NCBI
26	Yoon CY, Lee JS, Kim BS, et al: Sunitinib malate synergistically potentiates anti-tumor effect of gemcitabine in human bladder cancer cells. Korean J Urol. 52:55–63. 2011. View Article : Google Scholar : PubMed/NCBI
27	Moibi JA, Mak AL, Sun B and Moore RB: Urothelial cancer cell response to combination therapy of gemcitabine and TRAIL. Int J Oncol. 39:61–71. 2011.PubMed/NCBI
28	Yoon DH, Shin JS, Jin DH, et al: The survivin suppressant YM155 potentiates chemosensitivity to gemcitabine in the human pancreatic cancer cell line MiaPaCa-2. Anticancer Res. 32:1681–1688. 2012.PubMed/NCBI
29	Zou H, McGarry TJ, Bernal T and Kirschner MW: Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis. Science. 285:418–422. 1999. View Article : Google Scholar : PubMed/NCBI
30	Yu SY, Liu HF, Wang SP, Chang CC, Tsai CM and Chao JI: Evidence of securin-mediated resistance to gefitinib-induced apoptosis in human cancer cells. Chem Biol Interact. 203:412–422. 2013. View Article : Google Scholar : PubMed/NCBI
31	Yu HM and Wang TC: Mechanism of cisplatin resistance in human urothelial carcinoma cells. Food Chem Toxicol. 50:1226–1237. 2012. View Article : Google Scholar : PubMed/NCBI
32	Lai PC, Chiu TH and Huang YT: Overexpression of BDNF and TrkB in human bladder cancer specimens. Oncol Rep. 24:1265–1270. 2010.PubMed/NCBI
33	Huang YT, Lai PC, Wu CC, Cheng CC and Chiu TH: TrkB antibody elicits cytotoxicity and suppresses migration/invasion of transitional cell carcinoma cells. Int J Oncol. 37:943–949. 2010.PubMed/NCBI
34	Kumar B, Yadav A, Lang JC, et al: YM155 reverses cisplatin resistance in head and neck cancer by decreasing cytoplasmic survivin levels. Mol Cancer Ther. 11:1988–1998. 2012. View Article : Google Scholar : PubMed/NCBI
35	Iwasa T, Okamoto I, Takezawa K, et al: Marked anti-tumour activity of the combination of YM155, a novel survivin suppressant, and platinum-based drugs. Br J Cancer. 103:36–42. 2010. View Article : Google Scholar : PubMed/NCBI
36	Kita A, Mitsuoka K, Kaneko N, et al: Sepantronium bromide (YM155) enhances response of human B-cell non-Hodgkin lymphoma to rituximab. J Pharmacol Exp Ther. 343:178–183. 2012. View Article : Google Scholar : PubMed/NCBI
37	Kaneko N, Kita A, Yamanaka K and Mori M: Combination of YM155, a survivin suppressant with a STAT3 inhibitor: a new strategy to treat diffuse large B-cell lymphoma. Leuk Res. 37:1156–1161. 2013. View Article : Google Scholar : PubMed/NCBI
38	Yamanaka K, Nakahara T, Yamauchi T, et al: Antitumor activity of YM155, a selective small-molecule survivin suppressant, alone and in combination with docetaxel in human malignant melanoma models. Clin Cancer Res. 17:5423–5431. 2011. View Article : Google Scholar
39	Chen J, Pise-Masison CA, Shih JH, et al: Markedly additive antitumor activity with the combination of a selective survivin suppressant YM155 and alemtuzumab in adult T-cell leukemia. Blood. 121:2029–2037. 2013. View Article : Google Scholar : PubMed/NCBI
40	Li F, Ambrosini G, Chu EY, et al: Control of apoptosis and mitotic spindle checkpoint by survivin. Nature. 396:580–584. 1998. View Article : Google Scholar : PubMed/NCBI
41	Ning S, Fuessel S, Kotzsch M, et al: siRNA-mediated down-regulation of survivin inhibits bladder cancer cell growth. Int J Oncol. 25:1065–1071. 2004.PubMed/NCBI
42	Ghadimi MP, Young ED, Belousov R, et al: Survivin is a viable target for the treatment of malignant peripheral nerve sheath tumors. Clin Cancer Res. 18:2545–2557. 2012. View Article : Google Scholar : PubMed/NCBI
43	Cheng Q, Ling X, Haller A, et al: Suppression of survivin promoter activity by YM155 involves disruption of Sp1-DNA interaction in the survivin core promoter. Int J Biochem Mol Biol. 3:179–197. 2012.PubMed/NCBI
44	Sherr CJ: Cancer cell cycles. Science. 274:1672–1677. 1996. View Article : Google Scholar : PubMed/NCBI
45	Hunter T and Pines J: Cyclins and cancer. II: cyclin D and CDK inhibitors come of age. Cell. 79:573–582. 1994. View Article : Google Scholar : PubMed/NCBI
46	Arora R, Shuda M, Guastafierro A, et al: Survivin is a therapeutic target in Merkel cell carcinoma. Sci Transl Med. 4:133ra562012. View Article : Google Scholar : PubMed/NCBI
47	Scholzen T and Gerdes J: The Ki-67 protein: from the known and the unknown. J Cell Physiol. 182:311–322. 2000. View Article : Google Scholar : PubMed/NCBI
48	Gerdes J, Li L, Schlueter C, et al: Immunobiochemical and molecular biologic characterization of the cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki-67. Am J Pathol. 138:867–873. 1991.
49	Gou X, Yang HA, He WY, Xioa MC and Wang M: Gene silence-induced downregulation of survivin inhibits bladder cancer cells. Oncol Res. 19:535–541. 2011. View Article : Google Scholar : PubMed/NCBI
50	Ku JH, Seo SY, Kwak C and Kim HH: Cytotoxicity and apoptosis by survivin small interfering RNA in bladder cancer cells. BJU Int. 106:1812–1816. 2010. View Article : Google Scholar : PubMed/NCBI
51	Tao YF, Lu J, Du XJ, et al: Survivin selective inhibitor YM155 induce apoptosis in SK-NEP-1 Wilms tumor cells. BMC Cancer. 12:6192012. View Article : Google Scholar : PubMed/NCBI
52	Oliver FJ, de la Rubia G, Rolli V, Ruiz-Ruiz MC, de Murcia G and Murcia JM: Importance of poly(ADP-ribose) polymerase and its cleavage in apoptosis. Lesson from an uncleavable mutant. J Biol Chem. 273:33533–33539. 1998. View Article : Google Scholar : PubMed/NCBI
53	Yamanaka K, Nakata M, Kaneko N, et al: YM155, a selective survivin suppressant, inhibits tumor spread and prolongs survival in a spontaneous metastatic model of human triple negative breast cancer. Int J Oncol. 39:569–575. 2011.
54	Kuo LJ and Yang LX: γ-H2AX - a novel biomarker for DNA double-strand breaks. In Vivo. 22:305–309. 2008.
55	Chowdhury D, Keogh MC, Ishii H, Peterson CL, Buratowski S and Lieberman J: γ-H2AX dephosphorylation by protein phosphatase 2A facilitates DNA double-strand break repair. Mol Cell. 20:801–809. 2005.
56	Zhang Y, Chen ZD, Du CJ, Xu G and Luo W: siRNA targeting survivin inhibits growth and induces apoptosis in human renal clear cell carcinoma 786-O cells. Pathol Res Pract. 205:823–827. 2009. View Article : Google Scholar : PubMed/NCBI
57	Salehi F, Kovacs K, Scheithauer BW, Lloyd RV and Cusimano M: Pituitary tumor-transforming gene in endocrine and other neoplasms: a review and update. Endocr Relat Cancer. 15:721–743. 2008. View Article : Google Scholar : PubMed/NCBI
58	Chao JI and Liu HF: The blockage of survivin and securin expression increases the cytochalasin B-induced cell death and growth inhibition in human cancer cells. Mol Pharmacol. 69:154–164. 2006.
59	Sheverdin V, Bae SY, Shin DH and Lee K: Expression and localization of translationally controlled tumor protein in rat urinary organs. Microsc Res Tech. 75:1576–1581. 2012. View Article : Google Scholar : PubMed/NCBI
60	Roca H, Varsos ZS, Mizutani K and Pienta KJ: CCL2, survivin and autophagy: new links with implications in human cancer. Autophagy. 4:969–971. 2008. View Article : Google Scholar : PubMed/NCBI
61	Kreuzaler P and Watson CJ: Killing a cancer: what are the alternatives? Nat Rev Cancer. 12:411–424. 2012. View Article : Google Scholar : PubMed/NCBI