Hyperglycemia regulates MDR-1, drug accumulation and ROS levels causing increased toxicity of carboplatin and 5-fluorouracil in MCF-7 cells

J Cell Biochem. 2011 Oct;112(10):2942-52. doi: 10.1002/jcb.23210.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Acetylcysteine / pharmacology
  • Breast Neoplasms / metabolism
  • Carboplatin / toxicity*
  • Cell Line, Tumor
  • Female
  • Fluorouracil / toxicity*
  • Glucose / pharmacology
  • Humans
  • Hyperglycemia / physiopathology*
  • Inhibitory Concentration 50
  • NF-kappa B / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reactive Oxygen Species / metabolism
  • Verapamil / pharmacology


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • NF-kappa B
  • Reactive Oxygen Species
  • Carboplatin
  • Verapamil
  • Proto-Oncogene Proteins c-akt
  • Glucose
  • Fluorouracil
  • Acetylcysteine