title: Hyperglycemia regulates MDR-1, drug accumulation and ROS levels causing increased toxicity of carboplatin and 5-fluorouracil in MCF-7 cells.
abstract: There is constant increase in number of diabetic cases thereby giving it status of a serious epidemic. Diabetes increases the risk of occurrence of several cancers including breast cancer and may also have a serious impact on the outcome of cancer treatment. In the present study we investigated effect of hyperglycemia on cytotoxic efficacy of carboplatin and 5-fluorouracil in MCF-7 cells. MCF-7 cells were grown in 5.5 or 25 mM glucose chronically. We show that hyperglycemia favors proliferation of MCF-7 cells and increases expression of cell cycle regulatory proteins cyclin E and cdk-2. Hyperglycemia enhances cytotoxicity of carboplatin and 5-fluorouracil in MCF-7 cells by approximately 30% and decreases their IC50 by 1.5- and 1.3-folds, respectively. Hyperglycemia reduces expression of P-glycoprotein and promotes cell killing by increasing drug accumulation. Treatment with 40 µM verapamil, an inhibitor of P-gp activity specifically increases killing of MCF-7 cells cultured in 5.5 mM glucose. Further, this effect is synergized by elevated reactive oxygen species and treatment with N-Acetylcysteine, an inhibitor of ROS, increases survival by 30 and 18% in carboplatin- and 5-fluorouracil-treated cells cultured in high glucose, respectively. Cytotoxicity of these drugs is associated with reduced activation of Akt and decreased transcriptional activation of NF-κB. In conclusion, hyperglycemia potentiates cytotoxicity of drugs by reducing P-gp expression and, increased ROS levels may partially or completely contribute to enhanced toxicity.
authors.affiliation: National Centre for Cell Science, Pune University Campus, Ganeshkhind, Pune-411 007, India.
authors.forename: Vimal
authors.initials: V
authors.lastname: Pandey
authors.forename: Balkrishna
authors.initials: B
authors.lastname: Chaube
authors.forename: Manoj Kumar
authors.initials: MK
authors.lastname: Bhat
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000111:Acetylcysteine / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism; D016190:Carboplatin / Q000633:toxicity*; D045744:Cell Line, Tumor; D005260:Female; D005472:Fluorouracil / Q000633:toxicity*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology*; D020128:Inhibitory Concentration 50; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D016190:Carboplatin; D014700:Verapamil; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose; D005472:Fluorouracil; D000111:Acetylcysteine