Data from A Small-Molecule Inhibitor of Bcl-X_L Potentiates the Activity of Cytotoxic Drugs <i>In vitro</i> and <i>In vivo</i>

Abstract

&lt;div&gt;Abstract&lt;p&gt;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&lt;sub&gt;L&lt;/sub&gt;, 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&lt;sub&gt;L&lt;/sub&gt; versus Bcl-2 (&lt;i&gt;K&lt;/i&gt;&lt;sub&gt;i&lt;/sub&gt;'s of 0.80 and 67 nmol/L for Bcl-X&lt;sub&gt;L&lt;/sub&gt; 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&lt;sub&gt;50&lt;/sub&gt; of &lt;500 nmol/L in cells dependent on Bcl-X&lt;sub&gt;L&lt;/sub&gt; for survival. In addition, A-385358 enhances the &lt;i&gt;in vitro&lt;/i&gt; 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 &lt;i&gt;in vivo&lt;/i&gt;. 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. (Cancer Res 2006; 66(17): 8731-9)&lt;/p&gt;&lt;/div&gt;