Smoot RL, Blechacz BR, Werneburg N “Cancer research ” 2011
Apoptosis induction by BH3 mimetics is a therapeutic technique for human cancer. These mimetics exert single-agent activity in cells “primed” for cell death. Primed cells are influenced by antiapoptotic Bcl-2 proteins for survival and they are characterized by the ability of the BH3 mimetic to induce cytochrome c release from their isolated mitochondria. Our aim would have been to examine the single-agent activity of obatoclax, a BH3 mimetic in cholangiocarcinoma cell lines. In clonogenic assays, inhibition of colony formation was observed by obatoclax treatment. Despite single-agent activity by obatoclax, the mitochondria from these cells couldn’t release cytochrome c after incubation with this particular BH3 mimetic. However, immunofluorescence and cell fractionation studies identified Bax activation and translocation to mitochondria after treatment with obatoclax. shRNA targeted knockdown of Bax doubled the IC50 for obatoclax but would not abrogate its cytotoxicity, whereas knockdown of Bak couldn’t alter the IC50. In a cell-free system, obatoclax induced an activating conformational change of Bax, which had been attenuated by using a site-directed mutagenesis of a previously identified protein activation site. Finally, the drug also elicited a significant in vivo response within a rodent model of this disease. Subsequently, single-agent obatoclax treatment results in Bax activation, which contributes, in part, to cell death in cholangiocarcinoma cells. These data indicate that BH3 mimetics might also function as direct activators of Bax and induce cytotoxicity in cells not otherwise primed for cell death.
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