A novel BH3 mimetic S1 potently induces Bax/Bak‐dependent apoptosis by targeting both Bcl‐2 and Mcl‐1

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 5 310 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.

S1, a Novel Pan-BH3 Mimetic, Induces Apoptosis in Mcl-1-Overexpressing Cells Through Bak

“…As such, Mcl-1 decreased. These results further illustrated our previous finding that S1-induced apoptosis is Bim-independent (16). When the accumulation was less sufficient to release Bak, as 0.05 mg/kg S1 did in vivo, no apoptosis occurred to antagonize Mcl-1 stabilization and its level was continuously increased.…”

“…We recently showed that S1 can compete with BH3 peptide binding to Mcl-1 in vitro (16,19). It has been determined that Mcl-1 confers resistance to a promising BH3 mimetic, ABT-737.…”

“…We previously identified the small-molecule BH3 mimetic S1 that exhibits high affinity toward Bcl-2 and Mcl-1 (K i = 310 and 58 nM, respectively) (16). Herein, we assessed the effect of S1 in three Mcl-1-overexpressing cells.…”

BH3 Mimetics: Status of the Field and New Developments

“…This small-molecule inhibitor was initially suggested to be a pan-BH3 mimetic because it binds to both BCL-2 and MCL-1 (albeit with modest affinity: in the sub mmol/L range), disrupts BCL-2/BAX and MCL-1/BAK complexes, and triggers BAX/BAK-dependent apoptosis (34). A subsequent report showed that S1 does not act as a BH3 mimetic but instead induces the BH3-only protein NOXA (a specific antagonistic ligand for MCL-1) thus resulting in BAK release (15).…”

Mithramycin A Inhibits Myeloid Cell Leukemia-1 to Induce Apoptosis in Oral Squamous Cell Carcinomas and Tumor Xenograft through Activation of Bax and Oligomerization

“…The prosurvival functions of Mcl-1 are due to interacting with proapoptotic members of the Bcl-2 family such as Bim, Bak, and Bax, and this results in the inhibition of cytochrome c release from the mitochondria and decreased apoptosis (Kazi et al, 2011;Zhang et al, 2011). Recently, it has been reported that Mcl-1 is overexpressed in tumor cells of human primary OSCC and cultured SCC cell lines, suggesting that Mcl-1 may be an important drug target for treatment of human OSCC cases (Nagata et al, 2009).…”