Rosmarinic acid-induced apoptosis and cell cycle arrest in triple-negative breast cancer cells

Eur J Pharmacol. 2020 Oct 15;885:173419. doi: 10.1016/j.ejphar.2020.173419. Epub 2020 Aug 1.


Rosmarinic acid (RA) is a polyphenolic compound with various pharmacological properties, including, anti-inflammatory, immunomodulatory, and neuroprotective, as well as having antioxidant and anticancer activities. This study evaluated the effects and mechanisms of RA in two racially different triple-negative breast cancer (TNBC) cell lines. Results obtained show that RA significantly caused cytotoxic and antiproliferative effects in both cell lines in a dose- and time-dependent manner. Remarkably, RA induced cell cycle arrest-related apoptosis and altered the expression of many apoptosis-involved genes differently. In MDA-MB-231 cells, RA arrested the cells in the G0/G1 phase. In contrast, the data suggest that RA causes S-phase arrest in MDA-MB-468 cells, leading to a 2-fold increase in the apoptotic effect compared to MDA-MB-231 cells. Further, in MDA-MB-231 cells, RA significantly upregulated the mRNA expression of three genes: harakiri (HRK), tumor necrosis factor receptor superfamily 25 (TNFRSF25), and BCL-2 interacting protein 3 (BNIP3). In contrast, in the MDA-MB-468 cell line, the compound induced a significant transcription activation in three genes, including TNF, growth arrest and DNA damage-inducible 45 alpha (GADD45A), and BNIP3. Furthermore, RA repressed the expression of TNF receptor superfamily 11B (TNFRSF11B) in MDA-MB-231 cells in comparison to the ligand TNF superfamily member 10 (TNFSF10) and baculoviral IAP repeat-containing 5 (BIRC5) in MDA-MB-468 cells. In conclusion, the data suggest that the polyphenol RA may have a potential role in TNBC therapies, particularly in MDA-MB-468 cells.

Keywords: Apoptosis; Cell cycle; Gene expression; Rosmarinic; Triple-negative breast cancer.

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / antagonists & inhibitors
  • Cell Cycle / drug effects*
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Line, Tumor
  • Cell Survival
  • Cinnamates / pharmacology*
  • Depsides / pharmacology*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Membrane Proteins / antagonists & inhibitors
  • Osteoprotegerin / antagonists & inhibitors
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor, Member 25 / antagonists & inhibitors
  • Triple Negative Breast Neoplasms / drug therapy*


  • Antineoplastic Agents, Phytogenic
  • Apoptosis Regulatory Proteins
  • BNIP3 protein, human
  • Cell Cycle Proteins
  • Cinnamates
  • Depsides
  • GADD45A protein, human
  • HRK protein, human
  • Membrane Proteins
  • Osteoprotegerin
  • Proto-Oncogene Proteins
  • Receptors, Tumor Necrosis Factor, Member 25
  • TNFRSF11B protein, human
  • TNFRSF25 protein, human
  • rosmarinic acid