Low-dose doxorubicin with carotenoids selectively alters redox status and upregulates oxidative stress-mediated apoptosis in breast cancer cells

Food Chem Toxicol. 2018 Aug:118:675-690. doi: 10.1016/j.fct.2018.06.027. Epub 2018 Jun 18.

Abstract

The combination of carotenoids and doxorubicin (DOX) selectively alters oxidative stress-mediated apoptosis in breast cancer cells. Primarily, cytotoxic efficiency of carotenoids (β-carotene, BC; lutein, LUT; astaxanthin, AST; or fucoxanthin, FUCO) either with or without a minimal cytotoxic dose of DOX was evaluated in MCF-7 (0.12 μM) and MDA-MB-231 cells (0.28 μM). The higher cell growth inhibition of BC and/or LUT with DOX was selected for testing in further cell-based assays. Low-dose DOX significantly enhanced cytotoxicity in carotenoid (<5 μM)-treated cells compared to high-dose DOX (>1 μM) or carotenoid (20 μM) treatment alone. Depleted glutathione, increased lipid peroxides and increased ROS levels in cells confirmed the cytotoxic effect. Furthermore, mitochondrial dysfunction, cell growth arrest at G0/G1 phase and caspase cascades as well as up- and down-regulated expression levels of related proteins (p21, p27, Bax, p53, Bcl-2, and cyclin D1) revealed the synergistic effect of carotenoid and DOX treatment on ROS-mediated apoptosis. These observations demonstrated increased apoptosis in BC + DOX/LUT + DOX-treated cells due to the pronounced pro-oxidant action. Interestingly, normal breast epithelial cells (MCF 10A) exposed to similar treatments resulted in non-significant cytotoxicity. These newly observed mechanistic differences of anticancer drugs on the mitigation of toxicity with carotenoids may provide insight into the targeting of cancer therapy.

Keywords: Breast cancer cells; Carotenoids; Cytotoxicity; Doxorubicin; Oxidative stress-mediated apoptosis.

MeSH terms

  • Antibiotics, Antineoplastic / administration & dosage
  • Antibiotics, Antineoplastic / pharmacology*
  • Apoptosis / drug effects*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Carotenoids / administration & dosage
  • Carotenoids / pharmacology*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Doxorubicin / administration & dosage
  • Doxorubicin / pharmacology*
  • Drug Synergism
  • Female
  • Humans
  • Oxidation-Reduction
  • Oxidative Stress / drug effects*
  • Reactive Oxygen Species / metabolism
  • Up-Regulation / drug effects*

Substances

  • Antibiotics, Antineoplastic
  • Reactive Oxygen Species
  • Carotenoids
  • Doxorubicin