Luteolin impairs hypoxia adaptation and progression in human breast and colon cancer cells

Eur J Pharmacol. 2020 Aug 15:881:173210. doi: 10.1016/j.ejphar.2020.173210. Epub 2020 Jun 8.

Abstract

Hypoxia-inducible factors (HIFs) are the force which drives hypoxic cancer cells to a more aggressive and resistant phenotype in a number of solid tumors, including colorectal and breast cancer. Results from recent studies suggest a role for HIF-1 in immune evasion and cancer stem cell phenotype promotion, establishing HIF-1 as a potential therapeutic target. Thus, identifying new compounds that might inhibit HIF1 activity, or at least exert antiproliferative effects that are unaffected by HIF1-dependent adaptations, is an attractive goal for the management of hypoxic tumors. Here we show that the flavonoid luteolin exerts a significant cytotoxic effect on the colon cancer cell line HCT116 and the breast adenocarcinoma cell line MDA-MB231, by inducing both apoptotic and necrotic cell death, and that this effect is not impaired by HIF-1 activation. In these cells, luteolin also stimulates autophagy; however this seems to be part of a protective response, rather than contribute to the cytotoxic effect. Interestingly, luteolin induces a decrease in HIF-1 transcriptional activity. This is accompanied by a decrease in the levels of protein markers of stemness and invasion, and by a reduction of migratory capacity of the cells. Taken together, our results suggest that luteolin could be developed into a useful therapeutic agent aimed at hypoxic tumors.

Keywords: CD44; CD47; Cell death; HIF-1; Luteolin; Migration.

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / immunology
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Movement / drug effects
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Female
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Luteolin / pharmacology*
  • Necrosis
  • Signal Transduction
  • Transcription, Genetic
  • Tumor Escape / drug effects
  • Tumor Hypoxia
  • Tumor Microenvironment

Substances

  • Antineoplastic Agents, Phytogenic
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Luteolin