Flavopiridol suppresses cell proliferation and migration and induces apoptotic cell death by inhibiting oncogenic FOXM1 signaling in IDH-wild type and -mutant GBM cells

Abstract

Abstract Glioblastoma multiforme (GBM) remains one of the most challenging solid cancers to treat due to its highly aggressive and drug resistant nature. Flavopiridol is synthetic flavone that was recently approved by the FDA for the treatment of acute myeloid leukemia. Flavopiridol exhibits antiproliferative activity in several solid cancer cells and currently evaluated in clinical trials in several solid and hematological cancers. In this study, we investigated the molecular mechanisms underlying antiproliferative effects of Flavopiridol in GBM cell lines with wild type and mutant IDH1 (encoding isocitrate dehydrogenase 1). We found that Flavopiridol inhibits proliferation, colony formation, migration, and induces apoptosis in IDH1-wild type and IDH-mutant cells through inhibition of FOXM1 oncogenic signaling. Furthermore, flavopiridol treatment also inhibits of NF-KB, mediators unfolded protein response (UPR) (GRP78, PERK, IRE1α) and DNA repair enzyme PARP, which have been shown, be potential therapeutic targets by downregulating FOXM1 in GBM cells. Our findings suggest for the first time that flavopiridol suppresses proliferation, survival and migration and induces apoptosis in IDH1-wild type and mutant GBM cells by targeting FOXM1 oncogenic signaling which also regulates NF-KB, PARP, UPR responsein GBM cells. Flavopiridol may be a potential novel therapeutic strategy in the treatment of patients IDH1-wild type and mutant GBM.