Release Time:2019-03-09  Hits:

Indexed by: Journal Article

Date of Publication: 2011-04-01

Journal: INTERNATIONAL JOURNAL OF CANCER

Included Journals: PubMed、SCIE、Scopus

Volume: 128

Issue: 7

Page Number: 1724-1735

ISSN: 0020-7136

Key Words: Bcl-2; Mcl-1; pan-Bcl-2 inhibitor; BH3 mimetics

Abstract: Broad spectrum Bcl-2 small molecule inhibitors act as BH3 mimetics are effective antitumor agents. Herein, we have identified S1, a previously discovered small molecule Bcl-2 inhibitor, as the first authentic BH3 mimetic as well as a dual, nanomolar inhibitor of Bcl-2 and Mcl-1 (K(i) = 310 nM and 58 nM, respectively). The results of fluorescence polarization assays, coimmunoprecipitation, fluorescent resonance energy transfer, and shRNA indicated that S1 can disrupt Bcl-2/Bax, Mcl-1/Bak and Bcl-2/Bim heterodimerization in multiple cell lines, activate Bax accompanied by its translocation to mitochondrial, activate caspase 3 completely dependent on Bax/Bak, and in turn induce a Bim-independent apoptosis. Moreover, S1 could induce apoptosis on the primary acute lymphoblastic leukemia cells regardless of Mcl-1 level. Mechanism-based single agent antitumor activity in a mouse xenograft H22 (mouse liver carcinoma) model ascertain its therapeutic potential. S1 represents a novel chemical class of antitumor leads that function solely as BH3 mimetics and pan-Bcl-2 inhibitors. In the meanwhile, S1 could become a unique tool for interactions between Bcl-2 family proteins.