Abstract
Inhibition of the prosurvival members of the Bcl-2 family of proteins represents an attractive strategy for the treatment of cancer. We have previously reported the activity of ABT-737, a potent inhibitor of Bcl-2, Bcl-X(L), and Bcl-w, which exhibits monotherapy efficacy in xenograft models of small-cell lung cancer and lymphoma and potentiates the activity of numerous cytotoxic agents. Here we describe the biological activity of A-385358, a small molecule with relative selectivity for binding to Bcl-X(L) versus Bcl-2 (K(i)'s of 0.80 and 67 nmol/L for Bcl-X(L) and Bcl-2, respectively). This compound efficiently enters cells and co-localizes with the mitochondrial membrane. Although A-385358 shows relatively modest single-agent cytotoxic activity against most tumor cell lines, it has an EC(50) of <500 nmol/L in cells dependent on Bcl-X(L) for survival. In addition, A-385358 enhances the in vitro cytotoxic activity of numerous chemotherapeutic agents (paclitaxel, etoposide, cisplatin, and doxorubicin) in several tumor cell lines. In A549 non-small-cell lung cancer cells, A-385358 potentiates the activity of paclitaxel by as much as 25-fold. Importantly, A-385358 also potentiated the activity of paclitaxel in vivo. Significant inhibition of tumor growth was observed when A-385358 was added to maximally tolerated or half maximally tolerated doses of paclitaxel in the A549 xenograft model. In tumors, the combination therapy also resulted in a significant increase in mitotic arrest followed by apoptosis relative to paclitaxel monotherapy.
Highlights
Defects in the ability to appropriately regulate apoptotic processes are one of the fundamental occurrences that underlie cancer [1]
We have previously reported that ABT-737 exhibits potent cell killing of small-cell lung cancer and lymphoid cells but displays rather weak single-agent activity against most other tumor cell lines
Dysregulation of the Bcl-2 family of apoptosis regulators has long been implicated in the genesis and progression of cancer, the specific functions of these genes in this disease process remain poorly understood
Summary
Defects in the ability to appropriately regulate apoptotic processes are one of the fundamental occurrences that underlie cancer [1]. Progression to metastatic disease, and resistance to chemotherapeutic intervention all have been linked to apoptotic dysregulation [2–7]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Doi:10.1158/0008-5472.CAN-06-0367 of multiple prosurvival (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, and A1) as well as proapoptotic (Bax, Bak, Bad, Bid, Bim, Noxa, etc.) members [8]. These proteins control apoptosis through a complex panoply of protein-protein interactions between the prosurvival members and a subset of the BH3-only proapoptotic class This, in turn, facilitates the function of the second class of proapoptotic proteins, Bax and Bak, resulting in the induction of a network of proteins (e.g., caspases) that execute cellular destruction [9, 10]
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