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).

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.

• 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
• Journal: International journal of oncology (Int J Oncol) Vol. 45 Issue 4 Pg. 1680-90 (Oct 2014) ISSN: 1791-2423 [Electronic] Greece
• PMID: 24993441 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(1,1'-biphenyl)-4-yl-N-(5-(1,1-dioxo-1lambda(6)-isothiazolidin-2-yl)-1H-indazol-3-yl)acetamide
• Antineoplastic Agents
• CASP8 and FADD-Like Apoptosis Regulating Protein
• CFLAR protein, human
• Imidazoles
• Indazoles
• LB42708
• Proto-Oncogene Proteins c-bcl-2
• Pyrroles
• Thiazolidines

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis
• CASP8 and FADD-Like Apoptosis Regulating Protein (genetics, metabolism)
• Carcinoma, Renal Cell (genetics, metabolism, pathology)
• Cell Line, Tumor
• Drug Synergism
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Imidazoles (pharmacology)
• Indazoles (pharmacology)
• Kidney Neoplasms (genetics, metabolism, pathology)
• Membrane Potential, Mitochondrial (drug effects)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Pyrroles (pharmacology)
• Thiazolidines (pharmacology)