BAI, a novel Cdk inhibitor, enhances farnesyltransferase inhibitor LB42708-mediated apoptosis in renal carcinoma cells through the downregulation of Bcl-2 and c-FLIP (L)

  • Authors:
    • Ji Hoon Jang
    • Yoon Chul Cho
    • Ki Ho Kim
    • Kyung Seop Lee
    • Jinho Lee
    • Dong Eun Kim
    • Jun-Soo Park
    • Byeong-Churl Jang
    • Shin Kim
    • Taeg Kyu Kwon
    • Jong-Wook Park
  • View Affiliations

  • Published online on: July 4, 2014     https://doi.org/10.3892/ijo.2014.2534
  • Pages: 1680-1690
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Abstract

Previously, we reported the potential of a novel Cdk inhibitor, 2-[1,1'-biphenyl]-4-yl-N-[5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide (BAI) as a cancer chemotherapeutic agent. In this study, we investigated mechanisms by which BAI modulates FTI-mediated apoptosis in human renal carcinoma Caki cells. BAI synergizes with FTI to activate DEVDase, cleavage of poly ADP-ribose polymerase (PARP), and degradation of various anti-apoptotic proteins in Caki cells. BAI plus LB42708-induced apoptosis was inhibited by pretreatment with pan-caspase inhibitor, z-VAD-fmk, but not by overexpression of CrmA. The ROS scavenger, N-acetylcysteine (NAC) did not reduce BAI plus LB4270-induced apoptosis. Co-treatment of BAI and LB42708 reduced the mitochondrial membrane potential (MMP, ∆Ψm) in a time-dependent manner, and induced release of AIF and cytochrome c from mitochondria in Caki cells. Furthermore, BAL plus LB42708 induced downregulation of anti-apoptotic proteins [c-FLIP (L), c-FLIP (s), Bcl-2, XIAP, and Mcl-1 (L)]. Especially, we found that BAI plus LB42708-induced apoptosis was significantly attenuated by overexpression of Bcl-2 and partially blocked by overexpression of c-FLIP (L). Taken together, our results show that the activity of BAI plus LB42708 modulate multiple components in apoptotic response of human renal Caki cells, and indicate a potential as combinational therapeutic agents for preventing cancer such as renal carcinoma.
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October 2014
Volume 45 Issue 4

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

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APA
Jang, J.H., Cho, Y.C., Kim, K.H., Lee, K.S., Lee, J., Kim, D.E. ... Park, J. (2014). BAI, a novel Cdk inhibitor, enhances farnesyltransferase inhibitor LB42708-mediated apoptosis in renal carcinoma cells through the downregulation of Bcl-2 and c-FLIP (L). International Journal of Oncology, 45, 1680-1690. https://doi.org/10.3892/ijo.2014.2534
MLA
Jang, J. H., Cho, Y. C., Kim, K. H., Lee, K. S., Lee, J., Kim, D. E., Park, J., Jang, B., Kim, S., Kwon, T. K., Park, J."BAI, a novel Cdk inhibitor, enhances farnesyltransferase inhibitor LB42708-mediated apoptosis in renal carcinoma cells through the downregulation of Bcl-2 and c-FLIP (L)". International Journal of Oncology 45.4 (2014): 1680-1690.
Chicago
Jang, J. H., Cho, Y. C., Kim, K. H., Lee, K. S., Lee, J., Kim, D. E., Park, J., Jang, B., Kim, S., Kwon, T. K., Park, J."BAI, a novel Cdk inhibitor, enhances farnesyltransferase inhibitor LB42708-mediated apoptosis in renal carcinoma cells through the downregulation of Bcl-2 and c-FLIP (L)". International Journal of Oncology 45, no. 4 (2014): 1680-1690. https://doi.org/10.3892/ijo.2014.2534