Insulin-induced enhancement of MCF-7 breast cancer cell response to 5-fluorouracil and cyclophosphamide

Tumour Biol. 2017 Jun;39(6):1010428317702901. doi: 10.1177/1010428317702901.


The study was designed to evaluate the potential use of insulin for cancer-specific treatment. Insulin-induced sensitivity of MCF-7 breast cancer cells to chemotherapeutic agents 5-fluorouracil and cyclophosphamide was evaluated. To investigate and establish the possible mechanisms of this phenomenon, we assessed cell proliferation, induction of apoptosis, activation of apoptotic and autophagic pathways, expression of glucose transporters 1 and 3, formation of reactive oxygen species, and wound-healing assay. Additionally, we reviewed the literature regarding theuse of insulin in cancer-specific treatment. We found that insulin increases the cytotoxic effect of 5-fluorouracil and cyclophosphamide in vitro up to two-fold. The effect was linked to enhancement of apoptosis, activation of apoptotic and autophagic pathways, and overexpression of glucose transporters 1 and 3 as well as inhibition of cell proliferation and motility. We propose a model for insulin-induced sensitization process. Insulin acts as a sensitizer of cancer cells to cytotoxic therapy through various mechanisms opening a possibility for metronomic insulin-based treatments.

Keywords: 5-Fluorouracil; breast cancer; chemotherapy; cyclophosphamide; insulin.

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Apoptosis / drug effects
  • Autophagy / drug effects
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cyclophosphamide / administration & dosage
  • Drug Resistance, Neoplasm / genetics
  • Drug Synergism
  • Female
  • Fluorouracil / administration & dosage
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glucose Transporter Type 1 / biosynthesis
  • Glucose Transporter Type 1 / genetics*
  • Glucose Transporter Type 3 / biosynthesis
  • Glucose Transporter Type 3 / genetics*
  • Humans
  • Insulin / administration & dosage*
  • MCF-7 Cells


  • Antineoplastic Agents
  • Glucose Transporter Type 1
  • Glucose Transporter Type 3
  • Insulin
  • SLC2A3 protein, human
  • Cyclophosphamide
  • Fluorouracil