title: Vitamin D3 potentiates the growth inhibitory effects of metformin in DU145 human prostate cancer cells mediated by AMPK/mTOR signalling pathway.
abstract: Metformin and vitamin D₃ both exhibit a strong antiproliferative action in numerous cancer cell lines, including in human prostate cancer cells. Here we showed that the combination of the two drugs had a much stronger effect on DU145 human prostate cancer cell growth than either drug alone. In this research, cell proliferation was measured by methylthiazol tetrazolium (MTT) assay. Cell apoptosis was determined with Hoechst 33342 staining. Western blotting and cell cycle analyses were used to elucidate potential mechanisms of interaction between the drugs. It is shown that in cultured DU145 cells, vitamin D₃ combined with metformin exhibits synergistic effects on cell proliferation and apoptosis. The underlying antitumor mechanisms may involve altered cycle distribution with a G1/S cell cycle arrest, activation of phospho-AMPK with subsequent inhibition of downstream mTOR signalling pathway, down-regulate c-Myc expression, and reducing the level of anti-apoptotic protein p-Bcl-2. In conclusion, metformin and vitamin D₃ synergistically inhibit DU145 cell growth, indicating a promising clinical therapeutic strategy for the treatment of androgen-independent prostate cancer.
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Department of Pharmacology, School of Basic Medicine, Lanzhou University, Lanzhou, China.
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Li
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Department of Pharmacology, School of Basic Medicine, Lanzhou University, Lanzhou, China.
authors.forename: Jing-Miao
authors.initials: JM
authors.lastname: Gao
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Department of Pharmacology, School of Basic Medicine, Lanzhou University, Lanzhou, China.
authors.forename: Jia-Qi
authors.initials: JQ
authors.lastname: Liang
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Department of Pharmacology, School of Basic Medicine, Lanzhou University, Lanzhou, China.
authors.forename: Jun-Min
authors.initials: JM
authors.lastname: Xi
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Department of Pharmacology, School of Basic Medicine, Lanzhou University, Lanzhou, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Fu
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Department of Pharmacology, School of Basic Medicine, Lanzhou University, Lanzhou, China.
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Wu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006131:Growth Inhibitors / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D006131:Growth Inhibitors; D002762:Cholecalciferol; D008687:Metformin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: cell proliferation; metformin; prostate cancer; synergism; vitamin D3