The effects of β-caryophyllene oxide and trans-nerolidol on the efficacy of doxorubicin in breast cancer cells and breast tumor-bearing mice

Biomed Pharmacother. 2017 Nov;95:828-836. doi: 10.1016/j.biopha.2017.09.008. Epub 2017 Sep 10.


Background: One approach to improve effect of chemotherapy is combination of classical cytostatic drugs with natural compounds, e. g. sesquiterpenes. In our previous study, sesquiterpenes β-caryophyllene oxide (CAO) and trans-nerolidol (NER) improved the anti-proliferative effect of doxorubicin (DOX) in intestinal cancer cell lines.

Purpose: The present study was designed to evaluate the effect of CAO and NER on DOX efficacy, focusing on cell proliferation, migration, apoptosis and DOX accumulation in breast cancer cells MDA-MB-231 and MCF7 in vitro and in mice bearing solid Ehrlich tumors (EST) in vivo.

Methods: The impact of cytotoxic effect was assessed by the neutral red uptake test. The ability to migrate was tested using real-time measurement in x-CELLigence system. Expressions of molecules were examined using western blot analysis. The accumulation of DOX inside the cells using time lapse microscopy was observed. The mice with inoculated EST cells were treated repeatedly with DOX and DOX+CAO or DOX+NER and the growth of tumors were monitored. DOX concentrations in plasma and tumor were assayed using HPLC.

Results: In MDA-MB-231, combination of DOX with CAO enhanced anti-proliferative effect and acted strongly synergistic. NER increased accumulation of DOX inside the cells; moreover combination DOX with NER suppressed migration ability in vitro. In vivo, apoptosis was activated especially in group treated with DOX and CAO. However, none of tested sesquiterpenes was able to improve DOX accumulation in tumors and DOX-mediated inhibition of tumor growth.

Conclusion: In conclusion, sesquiterpenes CAO and NER increased the efficacy of DOX in breast cancer cells in vitro, but did not improve its effect in vivo, in Ehrlich solid tumor bearing mice.

Keywords: Anti-apoptotic effect; Breast cancer cells; Doxorubicin; Trans-nerolidol; Tumor bearing mice; β-Caryophyllene oxide.

MeSH terms

  • Animals
  • Breast Neoplasms / blood
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Doxorubicin / blood
  • Doxorubicin / therapeutic use*
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Mammary Neoplasms, Animal / drug therapy*
  • Mammary Neoplasms, Animal / pathology*
  • Mice
  • Polycyclic Sesquiterpenes
  • Sesquiterpenes / chemistry
  • Sesquiterpenes / pharmacology
  • Sesquiterpenes / therapeutic use*
  • Treatment Outcome


  • Polycyclic Sesquiterpenes
  • Sesquiterpenes
  • Doxorubicin
  • nerolidol
  • caryophyllene oxide