The Bcl-2/Bcl-XL/Bcl-w Inhibitor, Navitoclax, Enhances the Activity of Chemotherapeutic Agents in vitro and in vivo
Menée sur des lignées cellulaires de tumeurs solides humaines et à l'aide de xénogreffes, cette étude montre que le navitoclax, un inhibiteur de Bcl-2, Bcl-XL et Dcl-w, augmente l'efficacité du docétaxel et de l'erlotinib
A cancer cell's ability to avoid apoptosis is crucial to tumorigenesis and can also contribute to chemoresistance. The Bcl-2 family of pro-survival proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1 and A1) plays a key role in these processes. We previously reported the discovery of ABT-263 (navitoclax), a potent small molecule inhibitor of Bcl-2, Bcl-XL and Bcl-w. While navitoclax exhibits single-agent activity in tumors dependent on Bcl-2 or Bcl-XL for survival, the expression of Mcl-1 has been shown to confer resistance to navitoclax, most notably in solid tumors. Thus, therapeutic agents that can down-regulate or neutralize Mcl-1 are predicted to synergize potently with navitoclax. Here we report the activity of navitoclax in combination with 19 clinically relevant agents across a panel of 46 human solid tumor cell lines. Navitoclax broadly enhanced the activity of multiple therapeutic agent's in vitro and enhanced efficacy of both docetaxel and erlotinib in xenograft models. The ability of navitoclax to synergize with docetaxel or erlotinib corresponded to an altered sensitivity of the mitochondria towards navitoclax, which was associated with the down-modulation of Mcl-1 and/or up-regulation of Bim. These data provide a rationale to interrogate these combinations clinically.
http://mct.aacrjournals.org/content/early/2011/09/13/1535-7163.MCT-11-0415.abstract 2011