Open Access

Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo

  • Authors:
    • Takayuki Yamaguchi
    • Reina Kakefuda
    • Nobuyuki Tajima
    • Yoshihiro Sowa
    • Toshiyuki Sakai
  • View Affiliations

  • Published online on: April 26, 2011     https://doi.org/10.3892/ijo.2011.1015
  • Pages:23-31
Metrics: PDF 0 views | HTML 0 views
0

Abstract

The MAPK pathway is one of the most important pathways for novel anticancer drug development. We performed high-throughput screening for compounds that induce expression of p15INK4b, and identified JTP-74057 (GSK1120212), which is being evaluated in ongoing phase I, II and III clinical trials. We characterized its antitumor activities in vitro and in vivo. JTP-74057 strongly inhibited MEK1/2 kinase activities, but did not inhibit another 98 kinase activities. Treatment by JTP-74057 resulted in growth inhibition accompanied with upregulation of p15INK4b and/or p27KIP1 in most of the colorectal cancer cell lines tested. Daily oral administration of JTP-74057 for 14 days suppressed tumor growth of HT-29 and COLO205 xenografts in nude mice. Notably, tumor regression was observed only in COLO205 xenografts, and COLO205 was much more sensitive to JTP-74057-induced apoptosis than HT-29 in vitro. Treatment with an Akt inhibitor enhanced the JTP-74057-induced apoptosis in HT-29 cells. Finally, JTP-74057 exhibited an additive or a synergistic effect in combination with the standard-of-care agents, 5-fluorouracil, oxaliplatin or SN-38. JTP-74057, a highly specific and potent MEK1/2 inhibitor, exerts favorable antitumor activities in vitro and in vivo. Sensitivity to JTP-74057-induced apoptosis may be an important factor for the estimation of in vivo efficacy, and sensitivity was enhanced by an Akt inhibitor. These results suggest the usefulness of JTP-74057 in therapeutic applications for colorectal cancer patients.

Related Articles

Journal Cover

July 2011
Volume 39 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

2016 Impact Factor: 3.079
Ranked #33/217 Oncology
(total number of cites)

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Yamaguchi, T., Kakefuda, R., Tajima, N., Sowa, Y., & Sakai, T. (2011). Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo. International Journal of Oncology, 39, 23-31. https://doi.org/10.3892/ijo.2011.1015
MLA
Yamaguchi, T., Kakefuda, R., Tajima, N., Sowa, Y., Sakai, T."Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo". International Journal of Oncology 39.1 (2011): 23-31.
Chicago
Yamaguchi, T., Kakefuda, R., Tajima, N., Sowa, Y., Sakai, T."Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo". International Journal of Oncology 39, no. 1 (2011): 23-31. https://doi.org/10.3892/ijo.2011.1015