The recalcitrant nature of triple-negative breast cancer (TNBC) calls for novel treatments. Acetalax (oxyphenisatin acetate) and bisacodyl, which have been and are extensively used orally as laxatives, have recently been reported to exhibit selective antiproliferative activity when incubated with cancer cells and xenograft models. Here we show that they are both preferentially active in TNBC cell lines, and that their activity patterns overlap across the 1000 cell lines of the Sanger database but are unique and distinct from the standard chemotherapies. Multivariate transcriptomic analyses demonstrate that expression of the ion transporter TRPM4 and two other cell surface genes predict the activity of both drugs. In vivo testing shows that both Acetalax and bisacodyl induce complete regression of different TNBC PDXs. Acetalax pharmacokinetics shows a 5.8-hour terminal half-life and drug penetration in TNBC tumors and brain.