Multikinase inhibitor motesanib enhances the antitumor effect of cisplatin in cisplatin‑resistant human bladder cancer cells via apoptosis and the PI3K/Akt pathway

Ho,Jin‑Nyoung; Byun,Seok‑Soo; Lee,Sang   Eun; Youn,Je‑In; Lee,Sangchul

doi:10.3892/or.2019.7005

Multikinase inhibitor motesanib enhances the antitumor effect of cisplatin in cisplatin‑resistant human bladder cancer cells via apoptosis and the PI3K/Akt pathway

Authors:
- Jin‑Nyoung Ho
- Seok‑Soo Byun
- Sang Eun Lee
- Je‑In Youn
- Sangchul Lee
View Affiliations

Affiliations: Department of Urology, Seoul National University, Bundang Hospital, Seongnam 13620, Republic of Korea, Wide River Institute of Immunology, Seoul National University College of Medicine, Hongcheon 25159, Republic of Korea
Published online on: February 11, 2019 https://doi.org/10.3892/or.2019.7005
Pages: 2482-2490

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

Motesanib (AMG 706) is a small organic molecule that acts as a multi‑targeted tyrosine kinase inhibitor of VEGF, PDGF and stem cell factor receptor. It exhibits a potent antitumor effect in vitro and in vivo. To investigate the anticancer effect and possible mechanisms of motesanib in cisplatin‑resistant human bladder cancer cells (T24R2), T24R2 cells were treated with motesanib (50 µM) with or without cisplatin (2.5 µg/ml). Cell growth was assessed by the Cell Counting Kit‑8 and clonogenic assays. Cell cycle progression and apoptotic cell death were examined using flow cytometry. The expression levels of apoptosis‑ and survival‑related proteins were determined by western blot analysis. In combination with cisplatin, motesanib exhibited synergistic inhibition on T24R2 cell growth. Treatment using motesanib in combination with cisplatin markedly induced apoptosis and promoted cell cycle arrest in the S phase. It also increased the expression of apoptosis‑related genes including caspases, poly(ADP‑ribose) polymerase and cytochrome c, whereas it decreased the expression of survival‑related genes including p‑PI3K and p‑Akt. In conclusion, combination treatment with motesanib and cisplatin revealed a synergistically enhanced anticancer effect on cisplatin‑resistant human bladder cancer cells, accompanied with induced apoptosis and cell cycle arrest. Thus, the multikinase inhibitor motesanib could be developed as possible therapeutic agent for bladder cancer.

View Figures

View References

1	Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A and Bray F: Bladder cancer incidence and motality: A Global overview and recent trends. Eur Urol. 71:96–108. 2017. View Article : Google Scholar : PubMed/NCBI
2	Kamat AM, Hahn NM, Efstathiou JA, Lerner SP, Malmström PU, Choi W, Guo CC, Lotan Y and Kassouf W: Bladder cancer. Lancet. 388:2796–2810. 2016. View Article : Google Scholar : PubMed/NCBI
3	Godwin JL, Hoffman-Censits J and Plimack E: Recent developments in the treatment of advanced bladder cancer. Urol Oncol. 36:109–114. 2018. View Article : Google Scholar : PubMed/NCBI
4	McHugh LA, Kriajevska M, Mellon JK and Griffiths TR: Combined treatment of bladder cancer cell lines with lapatinib and varying chemotherapy regimens-evidence of schedule-dependent synergy. Urology. 69:390–394. 2007. View Article : Google Scholar : PubMed/NCBI
5	Dasari S and Tchounwou PB: Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J Pharmacol. 740:364–378. 2014. View Article : Google Scholar : PubMed/NCBI
6	Zhao Y and Adjei AA: Targeting angiogenesis in cancer therapy: Moving beyond vascular endothelial growth factor. Oncologist. 20:660–673. 2015. View Article : Google Scholar : PubMed/NCBI
7	Fus ŁP and Górnicka B: Role of angiogenesis in urothelial bladder carcinoma. Cent Eurpean J Urol. 69:258–263. 2016.
8	Bellmunt J, Hussain M and Dinney CP: Novel approaches with targeted therapies in bladder cancer therapy of bladder cancer by blockade of the epidermal growth factor receptor family. Crit Rev Oncol Hematol. 46 (Suppl 46):S85–S104. 2003. View Article : Google Scholar : PubMed/NCBI
9	Coxon A, Bush T, Saffran D, Kaufman S, Belmontes B, Rex K, Hughes P, Caenepeel S, Rottman JB, Tasker A, et al: Broad antitumor activity in breast cancer xenografts by motesanib, a highly selective, oral inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and Kit receptors. Clin Cancer Res. 15:110–118. 2009. View Article : Google Scholar : PubMed/NCBI
10	Li Y, Yang X, Su LJ and Flaig TW: Pazopanib synergizes with docetaxel in the treatment of bladder cancer cells. Urology. 78:233.e7–233.e13. 2011. View Article : Google Scholar
11	Black PC, Agarwal PK and Dinney CP: Targeted therapies in bladder cancer-an update. Urol Oncol. 25:433–438. 2007. View Article : Google Scholar : PubMed/NCBI
12	Jordan EJ and Iyer G: Targeted therapy in advanced bladder cancer: What have we learned? Urol Clin North Am. 42:253–262. 2015. View Article : Google Scholar : PubMed/NCBI
13	Polverino A, Coxon A, Starnes C, Diaz Z, DeMelfi T, Wang L, Bready J, Estrada J, Cattley R, Kaufman S, et al: AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res. 66:8715–8721. 2006. View Article : Google Scholar : PubMed/NCBI
14	Rosen LS, Kurzrock R, Mulay M, Van Vugt A, Purdom M, Ng C, Silverman J, Koutsoukos A, Sun YN, Bass MB, et al: Safety, pharmacokinetics, and efficacy of AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors. J Clin Oncol. 25:2369–2376. 2007. View Article : Google Scholar : PubMed/NCBI
15	Coxon A, Bready J, Kaufman S, Estrada J, Osgood T, Canon J, Wang L, Radinsky R, Kendall R, Hughes P, et al: Anti-tumor activity of motesanib in a medullary thyroid cancer model. J Endocrinol Invest. 35:181–190. 2012.PubMed/NCBI
16	Coxon A, Ziegler B, Kaufman S, Xu M, Wang H, Weishuhn D, Schmidt J, Sweet H, Starnes C, Saffran D and Polverino A: Antitumor activity of motesanib alone and in combination with cisplatin or docetaxel in multiple human non-small-cell lung cancer xenograft models. Mol Cancer. 11:702012. View Article : Google Scholar : PubMed/NCBI
17	Tebbutt N, Kotasek D, Burris HA, Schwartzberg LS, Hurwitz H, Stephenson J, Warner DJ, Chen L, Hsu CP and Goldstein D: Motesanib with or without panitumumab plus FOLFIRI or FOLFOX for the treatment of metastatic colorectal cancer. Cancer Chemother Pharmacol. 75:993–1004. 2015. View Article : Google Scholar : PubMed/NCBI
18	Lu JF, Claret L, Sutjandra L, Kuchimanchi M, Melara R, Bruno R and Sun YN: Population pharmacokinetic/pharmacodynamic modeling for the time course of tumor shrinkage by motesanib in thyroid cancer patients. Cancer Chemother Pharmacol. 66:1151–1158. 2010. View Article : Google Scholar : PubMed/NCBI
19	Schilder RJ, Sill MW, Lankes HA, Gold MA, Mannel RS, Modesitt SC, Hanjani P, Bonebrake AJ, Sood AK, Godwin AK, et al: A phase II evaluation of motesanib (AMG 706) in the treatment of persistent or recurrent ovarian, fallopian tube and primary peritoneal carcinomas: A Gynecologic Oncology Group study. Gynecol Oncol. 129:86–91. 2013. View Article : Google Scholar : PubMed/NCBI
20	Byun SS, Kim SW, Choi H, Lee C and Lee E: Augmentation of cisplatin sensitivity in cisplatin-resistant human bladder cancer cells by modulating glutathione concentrations and glutathione-related enzyme activities. BJU Int. 95:1086–1090. 2005. View Article : Google Scholar : PubMed/NCBI
21	Yeo EJ, Ryu JH, Chun YS, Cho YS, Jang IJ, Cho H, Kim J, Kim MS and Park JW: YC-1 induces S cell cycle arrest and apoptosis by activating checkpoint kinases. Cancer Res. 66:6345–6352. 2006. View Article : Google Scholar : PubMed/NCBI
22	Carmeliet P: VEGF as a key mediator of angiogenesis in cancer. Oncology. 69 (Suppl 3):S4–S10. 2005. View Article : Google Scholar
23	Appelmann I, Liersch R, Kessler T, Mesters RM and Berdel WE: Angiogenesis inhibition in cancer therapy: Platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) and their receptors: Biological functions and role in malignancy. Recent Results Cancer Res. 180:51–81. 2010. View Article : Google Scholar : PubMed/NCBI
24	Kaya TT, Altun A, Turgut NH, Ataseven H and Koyluoglu G: Effects of a multikinase inhibitor motesanib (AMG 706) alone and combined with the selective DuP-697 COX-2 inhibitor on colorectal cancer cells. Asian Pac J Cancer Prev. 17:1103–1110. 2016. View Article : Google Scholar : PubMed/NCBI
25	Elfiky AA and Rosenberg JE: Targeting angiogenesis in bladder cancer. Curr Oncol Rep. 11:244–249. 2009. View Article : Google Scholar : PubMed/NCBI
26	Wang F, Li HM, Wang HP, Ma JL, Chen XF, Wei F, Yi MY and Huang Q: siRNA-mediated knockdown of VEGF-A, VEGF-C and VEGFR-3 suppresses the growth and metastasis of mouse bladder carcinoma in vivo. Exp Ther Med. 1:899–904. 2010. View Article : Google Scholar : PubMed/NCBI
27	Wu CL, Ping SY, Yu CP and Yu DS: Tyrosine kinase receptor inhibitor-targeted combined chemotherapy for metastatic bladder cancer. Kaohsiung J Med Sci. 28:194–203. 2012. View Article : Google Scholar : PubMed/NCBI
28	Van Kessel KE, Zuiverloon TC, Alberts AR, Boormans JL and Zwarthoff EC: Targeted therapies in bladder cancer: An overview of in vivo research. Nat Rev Urol. 12:681–694. 2015. View Article : Google Scholar : PubMed/NCBI
29	Madka V, Zhang Y, Li Q, Mohammed A, Sindhwani P, Lightfoot S, Wu XR, Kopelovich L and Rao CV: P53-stabilizing agent CP-31398 prevents growth and invasion of urothelial cancer of the bladder in transgenic UPII-SV40T mice. Neoplasia. 15:966–974. 2013. View Article : Google Scholar : PubMed/NCBI
30	Kim SH, Ho JN, Jin H, Lee SC, Lee SE, Hong SK, Lee JW, Lee ES and Byun SS: Upregulated expression of BCL2, MCM7, and CCNE1 indicate cisplatin-resistance in the set of two human bladder cancer cell lines: T24 cisplatin sensitive and T24R2 cisplatin resistant bladder cancer cell lines. Investig Clin Urol. 57:63–72. 2016. View Article : Google Scholar : PubMed/NCBI
31	Bartholomeusz C and Gonzalez-Angulo AM: Targeting the PI3K signaling pathway in cancer therapy. Expert Opin Ther Targets. 16:121–130. 2012. View Article : Google Scholar : PubMed/NCBI
32	Sathe A and Nawroth R: Targeting the PI3K/AKT/mTOR pathway in bladder cancer. methods Mol Biol. 1655:335–350. 2018. View Article : Google Scholar : PubMed/NCBI
33	Dienstmann R, Rodon J, Serra V and Tabernero J: Picking the point of inhibition: A comparative review of PI3K/AKT/mTOR pathway inhibitors. Mol Cancer Ther. 13:1021–1031. 2014. View Article : Google Scholar : PubMed/NCBI
34	Fayard ETL, Baudry A and Hemmings BA: Protein kinase B/Akt at a glance. J Cell Sci. 118:5675–5678. 2005. View Article : Google Scholar : PubMed/NCBI