Ablation of cancer stem cells by therapeutic inhibition of the MDM2-p53 interaction in mucoepidermoid carcinoma

Purpose: Unique cells characterized by multipotency, self-renewal and high tumorigenic potential have been recently discovered in mucoepidermoid carcinomas (MEC). These cells are defined by high aldehyde dehydrogenase activity and high CD44 expression (ALDHhighCD44high) and function as cancer stem cells. It has been recently shown that p53 regulates cell differentiation, suggesting that induction of p53 by therapeutic blockade of the MDM2-p53 interaction may constitute a novel strategy to ablate cancer stem cells. Here, we evaluated the effect of a small molecule inhibitor of MDM2-p53 interaction (MI-773) on the fraction of cancer stem cells in mucoepidermoid carcinoma. Experimental design: Human mucoepidermoid carcinoma cells (UM-HMC-1,-3A,-3B) were used to assess the effect of MI-773 on cell survival, cell cycle, fraction of cancer stem cells and expression of p53, p21, MDM2, and Bmi-1 (key regulator of self-renewal). Mice bearing xenograft tumors generated with these MEC cells were treated with MI-773 to determine the effect of MDM2-p53 inhibition on cancer stem cells in vivo. Results: MDM2 is highly expressed in human MEC tissues. MI-773 induced expression of p53 and its downstream targets p21 and MDM2, caused G1 cell cycle arrest, and induced MEC tumor cell apoptosis in vitro. Importantly, a marked decrease in expression of Bmi-1 and in the fraction of ALDHhighCD44high (cancer stem cells) was caused by MI-773 in vitro and in mice harboring MEC xenografts. Conclusion: Collectively, these data demonstrate that MI-773 reduces the fraction of cancer stem cells, suggesting that patients with mucoepidermoid carcinoma might benefit from therapeutic inhibition of the MDM2-p53 interaction.

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