Acetalax (Oxyphenisatin acetate, NSC 59687) and bisacodyl Cause Oncosis in Triple Negative Breast Cancer Cell lines by Poisoning Ion Exchange Membrane Protein TRPM4.

Triple negative breast cancer (TNBC) is clinically aggressive and relatively unresponsive to current therapies. The development of new anticancer agents is needed. Oxyphenisatin acetate (Acetalax), which had been used as laxative has recently been reported to have anticancer activity in murine models. Here we demonstrate that Acetalax and its diphenolic laxative structural analog bisacodyl (Dulcolax) exhibit potent antiproliferative activity in TNBC cell lines and cause oncosis, a non-apoptotic cell death characterized by cellular and nuclear swelling and cell membrane blebbing leading to mitochondrial dysfunction, ATP depletion and enhanced immune and inflammatory responses. Mechanistically, we provide evidence that TRPM4 (Transient Receptor Potential Melastatin Member 4) is poisoned by Acetalax and bisacodyl in MDA-MB468, BT549 and HS578T TNBC cells. MDA-MB231 and MDA-MB436 TNBC cells without endogenous TRPM4 expression as well as TRPM 4 knockout TNBC cells were found to be Acetalax- and bisacodyl resistant. Conversely, ectopic expression of TRPM4 sensitized MDA-MB231 and MDA-MB436 cells to Acetalax. TRPM4 was also lost in cells with acquired Acetalax resistance. Moreover, TRPM4 is rapidly degraded by the ubiquitin-proteasome system upon acute exposure to Acetalax and bisacodyl. Together, these results demonstrate that TRPM4 is a previously unknown target of Acetalax and bisacodyl and that TRPM4 expression in cancer cells is a predictor of Acetalax and bisacodyl efficacy and could be used for the clinical development of these drugs as anticancer agents.