Identification of new therapeutic leads for triple negative breast cancer subtypes

High-content screening of plant and fungal extracts in a panel of cell lines modeling triple negative breast cancer subtypes identified 11 extracts with selective activity against particular cell lines. Maximiscin, (P/M) -1, was identified as having selective cytotoxic efficacy against the basal-like MDA-MB-468 cell line. Deguelin (2) was identified as having selective antiproliferative activity against the MDA-MB-453 cell line, representing the luminal androgen receptor subtype of TNBC. Mechanistic studies showed that maximiscin caused an accumulation of cells in G₁. Immunoblotting of maximiscin-treated whole cell lysates showed that maximiscin increases levels of P-p53, P-Chk1, P-Chk2, and γ-H2A.X. These results are consistent with the observed G₁ accumulation and collectively suggest that maximiscin induces DNA damage. Preliminary experiments suggest deguelin modulates AR localization and inhibits phosphorylation of Akt, ribosomal protein S6 and 4E-BP1 as soon as 2h after treatment. These results demonstrate that new compounds with potential therapeutic value for the treatment of TNBC subtypes can be identified from nature.