Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Oncology Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1021-335X Online ISSN: 1791-2431
Journal Cover
April-2019 Volume 41 Issue 4

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
April-2019 Volume 41 Issue 4

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

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 / Copyright

    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
  • Pages: 2482-2490
    |
    Published online on: February 11, 2019
       https://doi.org/10.3892/or.2019.7005
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



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

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

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

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Ho JN, Byun SS, Lee SE, Youn JI and Lee S: Multikinase inhibitor motesanib enhances the antitumor effect of cisplatin in cisplatin‑resistant human bladder cancer cells via apoptosis and the PI3K/Akt pathway. Oncol Rep 41: 2482-2490, 2019.
APA
Ho, J., Byun, S., Lee, S.E., Youn, J., & Lee, S. (2019). Multikinase inhibitor motesanib enhances the antitumor effect of cisplatin in cisplatin‑resistant human bladder cancer cells via apoptosis and the PI3K/Akt pathway. Oncology Reports, 41, 2482-2490. https://doi.org/10.3892/or.2019.7005
MLA
Ho, J., Byun, S., Lee, S. E., Youn, J., Lee, S."Multikinase inhibitor motesanib enhances the antitumor effect of cisplatin in cisplatin‑resistant human bladder cancer cells via apoptosis and the PI3K/Akt pathway". Oncology Reports 41.4 (2019): 2482-2490.
Chicago
Ho, J., Byun, S., Lee, S. E., Youn, J., Lee, S."Multikinase inhibitor motesanib enhances the antitumor effect of cisplatin in cisplatin‑resistant human bladder cancer cells via apoptosis and the PI3K/Akt pathway". Oncology Reports 41, no. 4 (2019): 2482-2490. https://doi.org/10.3892/or.2019.7005
Copy and paste a formatted citation
x
Spandidos Publications style
Ho JN, Byun SS, Lee SE, Youn JI and Lee S: Multikinase inhibitor motesanib enhances the antitumor effect of cisplatin in cisplatin‑resistant human bladder cancer cells via apoptosis and the PI3K/Akt pathway. Oncol Rep 41: 2482-2490, 2019.
APA
Ho, J., Byun, S., Lee, S.E., Youn, J., & Lee, S. (2019). Multikinase inhibitor motesanib enhances the antitumor effect of cisplatin in cisplatin‑resistant human bladder cancer cells via apoptosis and the PI3K/Akt pathway. Oncology Reports, 41, 2482-2490. https://doi.org/10.3892/or.2019.7005
MLA
Ho, J., Byun, S., Lee, S. E., Youn, J., Lee, S."Multikinase inhibitor motesanib enhances the antitumor effect of cisplatin in cisplatin‑resistant human bladder cancer cells via apoptosis and the PI3K/Akt pathway". Oncology Reports 41.4 (2019): 2482-2490.
Chicago
Ho, J., Byun, S., Lee, S. E., Youn, J., Lee, S."Multikinase inhibitor motesanib enhances the antitumor effect of cisplatin in cisplatin‑resistant human bladder cancer cells via apoptosis and the PI3K/Akt pathway". Oncology Reports 41, no. 4 (2019): 2482-2490. https://doi.org/10.3892/or.2019.7005
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team