title: Combination of oxidative stress and FOXM1 inhibitors induces apoptosis in cancer cells and inhibits xenograft tumor growth.
abstract: Tumor cells accumulate high level of reactive oxygen species (ROS) because they are metabolically more active than normal cells. Elevated ROS levels increase tumorigenecity but also render cancer cells more vulnerable to oxidative stress than normal cells. The oncogenic transcription factor Forkhead Box M1 (FOXM1), which is overexpressed in a wide range of human cancers, was reported to protect cancer cells from the adverse effects of oxidative stress by up regulating the expression of scavenger enzymes. We therefore hypothesized that the combination of FOXM1 ablation and ROS inducers could selectively eradicate cancer cells. We show that RNA interference-mediated knockdown of FOXM1 further elevates intracellular ROS levels and increases sensitivity of cancer cells to ROS-mediated cell death after treatment with ROS inducers. We also demonstrate that the combination of ROS inducers with FOXM1/proteasome inhibitors induces robust apoptosis in different human cancer cells. In addition, we show evidence that FOXM1/proteasome inhibitor bortezomib in combination with the ROS inducer β-phenylethyl isothiocyanate efficiently inhibits the growth of breast tumor xenografts in nude mice. We conclude that the combination of ROS inducers and FOXM1 inhibitors could be used as a therapeutic strategy to selectively eliminate cancer cells.
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
authors.forename: Marianna
authors.initials: M
authors.lastname: Halasi
authors.forename: Bulbul
authors.initials: B
authors.lastname: Pandit
authors.forename: Ming
authors.initials: M
authors.lastname: Wang
authors.forename: Veronique
authors.initials: V
authors.lastname: Nogueira
authors.forename: Nissim
authors.initials: N
authors.lastname: Hay
authors.forename: Andrei L
authors.initials: AL
authors.lastname: Gartel
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D045744:Cell Line, Tumor; D004334:Drug Administration Schedule; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017879:Isothiocyanates / Q000008:administration & dosage; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D018384:Oxidative Stress / Q000187:drug effects*; D011719:Pyrazines / Q000008:administration & dosage; D034622:RNA Interference; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D001897:Boronic Acids; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D017879:Isothiocyanates; D011719:Pyrazines; D017382:Reactive Oxygen Species; D004958:Estradiol; D000069286:Bortezomib; D000077584:2-Methoxyestradiol; C058305:phenethyl isothiocyanate