title: The multi-target drug BAI induces apoptosis in various human cancer cells through modulation of Bcl-xL protein.
abstract: Previous studies have demonstrated the anticancer effects of the newly developed cyclin-dependent kinase inhibitor BAI in various cancer cells. However, the molecular mechanisms of the cellular effects induced by BAI have not been fully elucidated. The objective of this study was to investigate the mechanisms underlying the regulation of B cell lymphoma-2 (Bcl-2) family proteins in BAI-induced apoptosis of cancer cells. BAI induced poly(ADP-ribose) polymerase cleavage and DEVDase activation dose- and time-dependently. However, BAI-induced apoptosis was not involved in reactive oxygen species generation or mitogen-activated protein kinases pathways. On the other hand, BAI reduced the mitochondrial membrane potential (∆ψm) dose- and time-dependently, and induced the release of apoptosis-inducing factor (AIF) and cytochrome c from mitochondria in A549 and Caki cells. Furthermore, BAI-induced apoptosis was strongly associated with downregulation of B-cell lymphoma-extra large (Bcl-xL), but not Bcl-2, and BAI modulated the interactions among p53 and Bcl-2 family proteins in human cancer cells. Taken together, these results revealed that the regulations of Bcl-2 family proteins are correlated with BAI-induced apoptosis, suggesting that BAI is a potential multi-target agent of cancer.
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea.
authors.forename: Shin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea.
authors.forename: Dong Eun
authors.initials: DE
authors.lastname: Kim
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea.
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
authors.affiliation: Department of Chemistry, Keimyung University, Daegu 42601, Republic of Korea.
authors.forename: Jinho
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea.
authors.forename: Jong-Wook
authors.initials: JW
authors.lastname: Park
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D009369:Neoplasms / Q000473:pathology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000378:metabolism; D053778:Thiazolidines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051020:bcl-X Protein / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: C545562:2-(1,1'-biphenyl)-4-yl-N-(5-(1,1-dioxo-1lambda(6)-isothiazolidin-2-yl)-1H-indazol-3-yl)acetamide; C494829:AIFM1 protein, human; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; C494811:BCL2L1 protein, human; D007191:Indazoles; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D053778:Thiazolidines; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases