A bax-mediated mechanism for obatoclax-induced apoptosis of cholangiocarcinoma cells

Rory L. Smoot, Boris R.A. Blechacz, Nathan W. Werneburg, Steve F. Bronk, Frank A. Sinicrope, Alphonse E. Sirica, Gregory J. Gores

Producción científica: Articlerevisión exhaustiva

51 Citas (Scopus)


Apoptosis induction by BH3 mimetics is a therapeutic strategy for human cancer. These mimetics exert single-agent activity in cells "primed" for cell death. Primed cells are dependent upon antiapoptotic Bcl-2 proteins for survival and are characterized by the ability of the BH3 mimetic to induce cytochrome c release from their isolated mitochondria. Our aim was 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 did not release cytochrome c after incubation with this 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 did not abrogate its cytotoxicity, whereas knockdown of Bak did not alter the IC50. In a cell-free system, obatoclax induced an activating conformational change of Bax, which was attenuated by a site-directed mutagenesis of a previously identified protein activation site. Finally, the drug also elicited a significant in vivo response in a rodent model of this disease. In conclusion, single-agent obatoclax treatment results in Bax activation, which contributes, in part, to cell death in cholangiocarcinoma cells. These data indicate that BH3 mimetics may also function as direct activators of Bax and induce cytotoxicity in cells not otherwise primed for cell death.

Idioma originalEnglish (US)
Páginas (desde-hasta)1960-1969
Número de páginas10
PublicaciónCancer Research
EstadoPublished - mar 1 2010
Publicado de forma externa

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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