title: Metformin enhancing the antitumor efficacy of carboplatin against Ehrlich solid carcinoma grown in diabetic mice: Effect on IGF-1 and tumoral expression of IGF-1 receptors.
abstract: Diabetes has been listed as a risk factor for various types of cancer. Cancer cell development can be promoted by increased levels of IGF-1 and hyperinsulinemia that are associated with diabetes type II. Metformin is an anti-diabetic agent and its potential antitumor impact has become the objective of numerous studies. In this vein, we hypothesize that using metformin in diabetes type II mice may synergistic with carboplatin for reducing the risk of cancer. Therefore, the study aimed to evaluate the in vivo antitumor activity of metformin against solid EAC tumor growth in female diabetic mice and its potential pro-apoptotic and anti-proliferative effects with clarification of its inconclusive biological mechanisms. Mice were assigned into nine groups; normal control, diabetic control, diabetic plus EAC control, EAC control, and treated groups received carboplatin and/or metformin (100, 200mg/kg). Metformin administration especially with high dose potentiated the antitumor activity of carboplatin displayed by increased pro-apoptotic activators "caspase-3 and bax" and reduced anti-apoptotic protein bcl-2. This was confirmed by the histopathological scores. Moreover, the combination therapy was effective in attenuating the expression of the pro-angiogenic mediator "VEGF" and the microvessel density as revealed by the CD34. Additionally, this combination down-regulated the high levels of the mutagenic element "IGF-1" and its receptor expression, and attenuated the intensity of inflammatory mediators. In conclusion, it was found that metformin therapy could enhance apoptotic marker, and suppress the neovascularization and proliferation process. This clarified the ability of metformin to support carboplatin activity in reducing tumor progression in type II diabetes.
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
authors.forename: Dina M
authors.initials: DM
authors.lastname: Abo-Elmatty
authors.affiliation: Department of Pharmacology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt.
authors.forename: Eman A
authors.initials: EA
authors.lastname: Ahmed
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt. Electronic address: dmon_kamal@yahoo.com.
authors.forename: Mona K
authors.initials: MK
authors.lastname: Tawfik
authors.affiliation: Department of Cytology and Histology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt.
authors.forename: Seham A
authors.initials: SA
authors.lastname: Helmy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D016190:Carboplatin / Q000627:therapeutic use*; D002286:Carcinoma, Ehrlich Tumor / Q000150:complications / Q000188:drug therapy*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008687:Metformin / Q000627:therapeutic use*; D051379:Mice; D008815:Mice, Inbred Strains; D009389:Neovascularization, Pathologic / Q000150:complications / Q000188:drug therapy*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D036341:Intercellular Signaling Peptides and Proteins; D042461:Vascular Endothelial Growth Factor A; C519530:insulin-like growth factor-1, mouse; C065700:myotrophin; D007334:Insulin-Like Growth Factor I; D008687:Metformin; D016190:Carboplatin; D017526:Receptor, IGF Type 1; D053148:Caspase 3
keywords: Angiogenesis; Apoptosis; carboplatin; diabetes type II; insulin-like-growth-factor-1; metformin