title: Methylseleninic acid potentiates multiple types of cancer cells to ABT-737-induced apoptosis by targeting Mcl-1 and Bad.
abstract: ABT-737, a novel small molecule inhibitor of Bcl-2 family proteins, holds great promise to complement current cancer therapies. However many types of solid cancer cells are resistant to ABT-737. One practical approach to improve its therapeutic efficacy is to combine with the agents that can overcome such resistance to restore the sensitivity. In the present study, a second-generation selenium compound methylseleninic acid (MSeA) synergistically sensitized MDA-MB-231 human breast cancer cells, HT-29 human colon cancer cells and DU145 human prostate cancer cells to apoptosis induction by ABT-737, as evidenced by greater than additive enhancement of Annexin V/FITC positive (apoptotic) cells and activation of multiple caspases and PARP cleavage. Mechanistic investigation demonstrated that MSeA significantly decreased basal Mcl-1 expression and ABT-737-induced Mcl-1 expression. Knocking down of Mcl-1 with RNAi approach supported the functional significance of this molecular target. More importantly, we identified inactivation of Bad by phosphorylation on ser-136 and ser-112 as a novel mechanism involved in ABT-737 resistance, which can be overcome by combining with MSeA. In addition, we found that expression of Bax was required for the efficient execution of synergistic sensitization. Our findings, for the first time, provide a strong mechanistic rationale for developing MSeA as a novel sensitizing agent of ABT-737.
authors.affiliation: Division of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Haidian District, Beijing, China.
authors.forename: Shutao
authors.initials: S
authors.lastname: Yin
authors.forename: Yinhui
authors.initials: Y
authors.lastname: Dong
authors.forename: Jinghua
authors.initials: J
authors.lastname: Li
authors.forename: Lihong
authors.initials: L
authors.lastname: Fan
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Junxuan
authors.initials: J
authors.lastname: Lu
authors.forename: Ole
authors.initials: O
authors.lastname: Vang
authors.forename: Hongbo
authors.initials: H
authors.lastname: Hu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D009596:Nitrophenols / Q000494:pharmacology*; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D051025:bcl-Associated Death Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C501332:ABT-737; C494819:BAD protein, human; D001713:Biphenyl Compounds; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D016566:Organoselenium Compounds; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051025:bcl-Associated Death Protein; C008493:methylselenic acid