Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
Mol Cancer Ther. 2011 Dec;10(12):2340-9. doi: 10.1158/1535-7163.MCT-11-0415. Epub 2011 Sep 13.
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.
癌细胞逃避细胞凋亡的能力对于肿瘤发生至关重要，并且还可能导致化疗耐药性。Bcl-2 家族的生存蛋白（Bcl-2、Bcl-X(L)、Bcl-w、Mcl-1 和 A1）在这些过程中发挥着关键作用。我们之前报道了 ABT-263（navitoclax）的发现，navitoclax 是一种有效的 Bcl-2、Bcl-X(L) 和 Bcl-w 的小分子抑制剂。虽然 navitoclax 在依赖 Bcl-2 或 Bcl-X(L) 生存的肿瘤中具有单药活性，但 Mcl-1 的表达已被证明对 navitoclax 产生耐药性，尤其是在实体瘤中。因此，预测能够下调或中和 Mcl-1 的治疗剂与 navitoclax 具有很强的协同作用。在这里，我们报告了 navitoclax 与 46 个人类实体瘤细胞系中的 46 个人类实体瘤细胞系中的 19 种临床相关药物联合使用的活性。navitoclax 广泛增强了多种治疗剂在体外的活性，并增强了紫杉烷和厄洛替尼在异种移植模型中的疗效。navitoclax 与紫杉烷或厄洛替尼协同作用的能力与线粒体对 navitoclax 的敏感性改变有关，这与 Mcl-1 的下调和/或 Bim 的上调有关。这些数据为临床研究这些组合提供了依据。
