title: 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.affiliation: Department of Immunology, School of Medicine, Keimyung University, Daegu, Republic of Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jang
authors.affiliation: Department of Urology, Dongguk University, College of Medicine, Gyeongju, Republic of Korea.
authors.forename: Yoon Chul
authors.initials: YC
authors.lastname: Cho
authors.affiliation: Department of Urology, Dongguk University, College of Medicine, Gyeongju, Republic of Korea.
authors.forename: Ki Ho
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Urology, Dongguk University, College of Medicine, Gyeongju, Republic of Korea.
authors.forename: Kyung Seop
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Keimyung University, Daegu, Republic of Korea.
authors.forename: Jinho
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, Daegu, Republic of Korea.
authors.forename: Dong Eun
authors.initials: DE
authors.lastname: Kim
authors.affiliation: Chronic Disease Research Center, School of Medicine, Keimyung University, Daegu, Republic of Korea.
authors.forename: Jun-Soo
authors.initials: JS
authors.lastname: Park
authors.affiliation: Chronic Disease Research Center, School of Medicine, Keimyung University, Daegu, Republic of Korea.
authors.forename: Byeong-Churl
authors.initials: BC
authors.lastname: Jang
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, Daegu, Republic of Korea.
authors.forename: Shin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, Daegu, Republic of Korea.
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, Daegu, Republic of Korea.
authors.forename: Jong-Wook
authors.initials: JW
authors.lastname: Park
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007191:Indazoles / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D053778:Thiazolidines / Q000494:pharmacology*
chemical_list: C545562:2-(1,1'-biphenyl)-4-yl-N-(5-(1,1-dioxo-1lambda(6)-isothiazolidin-2-yl)-1H-indazol-3-yl)acetamide; D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D007093:Imidazoles; D007191:Indazoles; C514652:LB42708; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D053778:Thiazolidines