Aminoflavone

Identification of the molecular mechanism of action (MoA) of bioactive compounds is a crucial step for drug development but remains a challenging task despite recent advances in technology. In this study, we applied multidimensional proteomics, sensitivity correlation analysis, and transcriptomics to identify a common MoA for the anticancer compounds RITA, aminoflavone (AF), and oncrasin-1 (Onc-1). Global thermal proteome profiling revealed that the three compounds target mRNA processing and transcription, thereby attacking a cancer vulnerability, transcriptional addiction. This led to the preferential loss of expression of oncogenes involved in PDGF, EGFR, VEGF, insulin/IGF/MAPKK, FGF, Hedgehog, TGFβ, and PI3K signaling pathways. Increased reactive oxygen species level in cancer cells was a prerequisite for targeting the mRNA transcription machinery, thus conferring cancer selectivity to these compounds. Furthermore, DNA repair factors involved in homologous recombination were among the most prominently repressed proteins. In cancer patient samples, RITA, AF, and Onc-1 sensitized to poly(ADP-ribose) polymerase inhibitors both in vitro and ex vivo. These findings might pave a way for new synthetic lethal combination therapies.Significance: These findings highlight agents that target transcriptional addiction in cancer cells and suggest combination treatments that target RNA processing and DNA repair pathways simultaneously as effective cancer therapies.

More than 40% of patients with luminal breast cancer treated with endocrine therapy agent tamoxifen demonstrate resistance. Emerging evidence suggests tumor initiating cells (TICs) and aberrant activation of Src and Akt signaling drive tamoxifen resistance and relapse. We previously demonstrated that aryl hydrocarbon receptor ligand aminoflavone (AF) inhibits the expression of TIC gene α6‐integrin and disrupts mammospheres derived from tamoxifen‐sensitive breast cancer cells. In the current study, we hypothesize that tamoxifen‐resistant (TamR) cells exhibit higher levels of α6‐integrin than tamoxifen‐sensitive cells and that AF inhibits the growth of TamR cells by suppressing α6‐integrin–Src–Akt signaling. In support of our hypothesis, TamR cells and associated mammospheres were found to exhibit elevated α6‐integrin expression compared with their tamoxifen‐sensitive counterparts. Furthermore, tumor sections from patients who relapsed on tamoxifen showed enhanced α6‐integrin expression. Gene expression profiling from the TCGA database further revealed that basal‐like breast cancer samples, known to be largely unresponsive to tamoxifen, demonstrated higher α6‐integrin levels than luminal breast cancer samples. Importantly, AF reduced TamR cell viability and disrupted TamR mammospheres while concomitantly reducing α6‐integrin messenger RNA and protein levels. In addition, AF and small interfering RNA against α6‐integrin blocked tamoxifen‐stimulated proliferation of TamR MCF‐7 cells and further sensitized these cells to tamoxifen. Moreover, AF reduced Src and Akt signaling activation in TamR MCF‐7 cells. Our findings suggest elevated α6‐integrin expression is associated with tamoxifen resistance and AF suppresses α6‐integrin–Src–Akt signaling activation to confer activity against TamR breast cancer.