Background: Poly(ADP-ribose) polymerases 1 and 2 (PARP1, 2), and 3 mediate protein modifications that facilitate the recruitment of DNA repair factors to single and double strand breaks. PARP3 is unique in that it is also required for efficient mitotic progression and stabilization of the mitotic spindle. Eribulin, an anti-microtubule agent used clinically to treat breast cancer, exerts its cytotoxicity by altering microtubule dynamics resulting in cell cycle arrest and apoptosis. Herein, we hypothesize that the pan PARP inhibitor olaparib has the potential to enhance the cytotoxicity of eribulin by halting mitosis through inhibition of PARP3. Methods: The effect of olaparib on eribulin cytotoxicity was assessed using the Sulforhodamine (SRB) assay, with two triple negative breast cancer cell lines and an estrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer cell line. Alteration by the treatments on PARP3 activity and microtubule dynamics were assessed utilizing a chemiluminescent enzymatic assay and immunofluorescence, respectively. The effect of the treatments on cell cycle progression and apoptosis induction were assessed by flow cytometry using propidium iodide and Annexin V staining, respectively. Results: Our results demonstrate that non-cytotoxic concentrations of olaparib sensitize breast cancer cells regardless of ER status. Mechanistically, our results indicate that olaparib potentiates eribulin-induced cell cycle arrest at the G2/M boundary, PARP3 inhibition and microtubule destabilizing resulting in mitotic catastrophe and apoptosis. Conclusions: In breast cancer (regardless of ER status) settings, treatment outcomes could be improved by the incorporation of olaparib in eribulin treatment regimens.
Cite this article
Volume | Year
Open Access Original Research
PARP Inhibition Sensitizes Breast Cancer Cells to Eribulin
1 Montreal Centre for Experimental Therapeutics in Cancer Segal Cancer Center, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montréal, QC H3T 1E2, Canada
*Correspondence: Lawrence.email@example.com (Lawrence Panasci)
Front. Biosci. (Landmark Ed) 2023, 28(3), 52; https://doi.org/10.31083/j.fbl2803052
Submitted: 17 October 2022 | Revised: 2 March 2023 | Accepted: 6 March 2023 | Published: 16 March 2023
Copyright: © 2023 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
breast cancer cell lines
01713/Cancer Research Society