The Bcl-2/Bcl-X(L)/Bcl-w inhibitor, navitoclax, enhances the activity of chemotherapeutic agents in vitro and in vivo

• Published in: Molecular cancer therapeutics 2011-12, Vol.10 (12), p.2340-2349
• Main Authors: Chen, Jun, Jin, Sha, Abraham, Vivek, Huang, Xiaoli, Liu, Bernard, Mitten, Michael J, Nimmer, Paul, Lin, Xiaoyu, Smith, Morey, Shen, Yu, Shoemaker, Alexander R, Tahir, Stephen K, Zhang, Haichao, Ackler, Scott L, Rosenberg, Saul H, Maecker, Heather, Sampath, Deepak, Leverson, Joel D, Tse, Chris, Elmore, Steven W
• Format: Article
• Language: English
• Subjects: Aniline Compounds - administration & dosage; Aniline Compounds - pharmacology; Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis Regulatory Proteins - antagonists & inhibitors; bcl-X Protein - antagonists & inhibitors; Drug Synergism; Female; HCT116 Cells; Hep G2 Cells; Humans; K562 Cells; Male; Mice; Neoplasms - drug therapy; Neoplasms - pathology; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Sulfonamides - administration & dosage; Sulfonamides - pharmacology; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 1538-8514
• DOI: 10.1158/1535-7163.MCT-11-0415

The ability of a cancer cell to avoid apoptosis is crucial to tumorigenesis and can also contribute to chemoresistance. The Bcl-2 family of prosurvival proteins (Bcl-2, Bcl-X(L), 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-X(L), and Bcl-w. While navitoclax exhibits single-agent activity in tumors dependent on Bcl-2 or Bcl-X(L) 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 downregulate 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 agents 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 toward navitoclax, which was associated with the downmodulation of Mcl-1 and/or upregulation of Bim. These data provide a rationale to interrogate these combinations clinically.