Gene expression profiling in Indolocarbazole alkaloid Loonamycin A treated MDA-MB-231 cells

In triple negative breast cancer (TNBC), aberrant activation of Notch signaling plays an important role for the maintenance of cancer stem cell (CSC) stemness. Targeting CSCs via inhibition of Notch signaling can be a potential therapeutic option for this incurable disease. We previously used genome mining strategy to discover a new indolocarbazole alkaloid loonamycin A (Loo A). In this study, we demonstrate that Loo A has stronger cytotoxicity toward TNBC cells than its structural analog rebeccamycin. Apart from inhibition of TNBC cell proliferation and migration, Loo A reduced CD44high/CD24low/- sub-population, mammosphere formation, as well as the expression of stemness-associated genes. Co-administration of Loo A enhanced antitumor effects of paclitaxel by inducing apoptosis. RNA sequencing result showed that Loo A treatment caused the inhibition of Notch signaling, accompanied by the decreased expression of Notch1 and its targeted genes in TNBC cells. These results reveal a novel bioactivity of indolocarbazole-type alkaloids and provide promising Notch-inhibiting small molecular candidates for TNBC therapy.