胶质母细胞瘤多形性（GBM）由于其高侵袭性和耐药性而仍然是治疗最具挑战性的固体癌症之一。Flavopiridol是一种合成的黄酮类物质，最近被FDA批准用于治疗急性髓系白血病。Flavopiridol在多种固体癌细胞中显示抗增殖活性，并已在几种固体和血液系统癌症的临床试验中进行评估。在本研究中，我们调查了Flavopiridol在野生型和突变型异柠檬酸脱氢酶1（IDH1）编码的GBM细胞系中抗增殖效应的分子机制。我们发现，Flavopiridol通过抑制FOXM1致癌信号转导，抑制了IDH1野生型和IDH突变型细胞的增殖、集落形成和迁移，并诱导了凋亡。此外，Flavopiridol还抑制了NF-KB、介导未折叠蛋白应激（UPR）的介质，包括GRP78、PERK和IRE1α，以及DNA修复酶PARP，这些酶已被证明是通过下调GBM细胞中的FOXM1而具有潜在的治疗靶点。我们的发现首次表明Flavopiridol通过靶向FOXM1致癌信号转导抑制了IDH1野生型和IDH1突变型的GBM细胞的增殖、存活和迁移，并在GBM细胞中调节了NF-KB、PARP和UPR反应。Flavopiridol可能是治疗IDH1野生型和IDH1突变型GBM患者的潜在新的治疗策略。© 2023.本文是美国政府工作，不受美国版权保护，可能适用外国版权保护。

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 encoding isocitrate dehydrogenase 1 (IDH1). We found that flavopiridol inhibits proliferation, colony formation, and 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), including, GRP78, PERK and IRE1α, and DNA repair enzyme PARP, which have been shown to 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 IDH1-mutant GBM cells by targeting FOXM1 oncogenic signaling which also regulates NF-KB, PARP, and UPR response in GBM cells. Flavopiridol may be a potential novel therapeutic strategy in the treatment of patients IDH1 wild-type and IDH1-mutant GBM.© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.