title: The Induction of Metformin Inhibitory Effects on Tumor Cell Growth in Hypoxic Condition.
abstract: It is aimed to evaluate the actual anti-cancerous effects of metformin on cancer cells in hypoxic condition. Non-cancerous cells (HEK293) and cancer cells (MCF-7) were cultured in both hypoxia and normoxia conditions and treated with different concentrations of metformin. The proliferation, apoptosis, and necrosis rate were assessed using MTT test and Annexin V assay. The S6K1 phosphorylation was assessed using western blotting. Zymography was used to measure the activity of metalloproteinase-9 (MMP-9). Metformin treatment inhibited proliferation of cancer cells in the optimal concentration of 10 mM under hypoxia condition, while it showed no effects on non-cancerous cell viability. The statistical analysis of MTT assay indicated that the pro-apoptotic function of metformin for cancer cells under hypoxia condition compared to normoxia was significant with different metformin concentrations (p<0.01). However, the effect of metformin treatments for non-cancerous cells under hypoxia condition compared to normoxia was not significant. Western-blot analysis indicated a significant decrease in S6K1 phosphorylation in cancer cells under hypoxia condition (p<0.05). Nevertheless, there was no considerable difference between normoxia and hypoxia conditions in non-cancerous cells. MMP-9 zymography analysis revealed that the highest inhibition of MMP-9 activity was observed in hypoxia condition by 20mM of metformin concentration only in cancer cell. The results indicate that in hypoxia condition metformin exerts its anti-cancerous function by inhibiting proliferation and tumor progression and inducing cell apoptosis more effectively than normoxia condition. In line with cancer cell conditions, most importantly hypoxic condition, metformin can be considered as a potential anti-cancerous drug.
authors.affiliation: Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran AND Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Safari
authors.affiliation: Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
authors.forename: Reza
authors.initials: R
authors.lastname: Safaralizadeh
authors.affiliation: Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mir Hadi
authors.initials: MH
authors.lastname: Seyedzadeh
authors.affiliation: Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
authors.forename: Ayla
authors.initials: A
authors.lastname: Valinezad Orang
authors.affiliation: Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ahad
authors.initials: A
authors.lastname: Zare
authors.affiliation: Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
authors.forename: Mohammad Ali
authors.initials: MA
authors.lastname: Hosseinpour Feizi
authors.affiliation: Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran AND Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Gholam Ali
authors.initials: GA
authors.lastname: Kardar
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D009336:Necrosis; D010766:Phosphorylation; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D008687:Metformin; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D020780:Matrix Metalloproteinase 9
keywords: Breast cancer; Hypoxia; Metformin