title: The small-molecule compound BM-1197 inhibits the antiapoptotic regulators Bcl-2/Bcl-xL and triggers apoptotic cell death in human colorectal cancer cells.
abstract: Small molecule BH3 mimetics comprise a promising new chemotherapeutic strategy for treating relapsed or chemoresistant cancer. In this study, we investigated the cellular mechanism of action by which BM-1197, a Bcl-xL/Bcl-2 dual inhibitor, triggers apoptosis in a panel of colorectal cancer (CRC) lines. Using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, we determined that BM-1197 inhibited CRC cell growth in a concentration- and time-dependent manner. The 50 % inhibitory concentration (IC50) values for the most sensitive cell lines, SW620 and SW480, ranged from 0.07 to 1.10 μM in response to a 72-h treatment. In CRC cells, BM-1197 induced apoptotic death without affecting the expression of Bcl-2 family proteins. However, BM-1197 effectively triggered a conformational change in Bax, releasing Bim from Bcl-xL by disrupting the interaction between Bcl-xL and Bak/Bax. Compared with the control group, BM-1197 treatment significantly increased the fraction of SW480 cells in the sub-G1 phase, the apoptosis rate, and cellular internucleosomal DNA fragmentation. The proapoptotic activity was associated with cytochrome c release, caspase-3 activation, and PARP-1 cleavage. Collectively, BM-1197 effectively suppressed the growth of the human CRC cell line SW480 by inducing mitochondria-dependent apoptotic cell death. These data have specific implications for the in vivo analysis and clinical evaluation of BM-1197 in CRC.
authors.affiliation: The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Ye
authors.forename: Gang
authors.initials: G
authors.lastname: Yuan
authors.forename: Fei
authors.initials: F
authors.lastname: Xu
authors.forename: Yueli
authors.initials: Y
authors.lastname: Sun
authors.forename: Ziyan
authors.initials: Z
authors.lastname: Chen
authors.forename: Miaohong
authors.initials: M
authors.lastname: Chen
authors.forename: Tianxiao
authors.initials: T
authors.lastname: Li
authors.forename: Pingping
authors.initials: P
authors.lastname: Sun
authors.forename: Shuxia
authors.initials: S
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D011487:Protein Conformation; D055503:Protein Multimerization; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000737:chemistry; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C000600257:BM-1197; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D045304:Cytochromes c; D053148:Caspase 3