A small-molecule p53 activator induces apoptosis through inhibiting MDMX expression in breast cancer cells

The tumor suppressor p53 is often inactivated in breast cancer cells because the overexpression of its repressors (e.g., MDM2 and MDMX). Restoration of p53 activity by small molecules through counteracting p53 repressors can lead to in vivo tumor regression and is therefore considered a promising strategy for treatments of cancer. Recent efforts in high-throughput drug screening and rational drug design have identified several structurally diverse small-molecule p53 activators, including a pseudourea derivative XI-011 (NSC146109). This small molecule strongly activates p53 while selectively inhibiting growth of transformed cells without inducing genotoxicity, indicating its potential as a drug lead for p53-targeted therapy. However, the mechanism(s) by which XI-011 activates p53 and the effects of XI-011 on growth of breast cancer cells are currently unknown. Here, we report that XI-011 promoted breast cancer cells to undergo apoptosis through activating p53 and inducing expression of proapoptotic genes. Importantly, we found that activation of p53 by this small molecule was achieved through a novel mechanism, that is, inhibition of MDMX expression. XI-011 repressed the MDMX promoter, resulting in down-regulation of MDMX messenger RNA level in MCF-7 cells. In line with these results, XI-011 decreased the viability of breast cancer cells expressing low levels of MDMX in a less-efficient manner. Interestingly, XI-011 acted additively with the MDM2 antagonist Nutlin-3a to inhibit growth of breast cancer cells. We conclude that XI-011 belongs to a novel class of small-molecule p53 activators that target MDMX and could be of value in treating breast cancer.