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PARP3 inhibitors ME0328 and olaparib potentiate vinorelbine sensitization in breast cancer cell lines

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Abstract

Purpose

PARP-3 is member of the PARP family of poly (ADP-ribose) polymerases involved in ADPribosylation. PARPs are involved in the basic mechanisms of DNA repair. PARP3, a critical player for efficient mitotic progression, is required for the stabilization of the mitotic spindle by regulation of the mitotic components, NuMA and Tankyrase 1.

Methods

The sensitization effect of vinorelbine on PARP3 inhibition-induced cytotoxicity was assessed by the SRB assay. The contribution of programed cell death and cell cycle arrest to the sensitization effect were determined by assessing changes in Annexin V, a marker of apoptosis. Alterations in cell cycle progression were assessed by cell cycle analysis. We used immunofluorescence to assess the effect of vinorelbine and/or PARP3 inhibitors on tubulin and microtubule depolarization. The PARP3 chemiluminescent assay kit was used for PARP3 activity.

Results

PARP3 inhibitors sensitize breast cancer cells to vinorelbine, a vinca alkaloid used in the treatment of metastatic breast cancer. Olaparib which was originally described as a PARP1 and 2 inhibitor has recently been shown to be a potent PARP3 inhibitor while ME0328 is a more selective PARP3 inhibitor. The combination of vinorelbine with nontoxic concentrations of ME0328 or olaparib reduces vinorelbine resistance by 10 and 17 fold, respectively, potentiating vinorelbine-induced arrest at the G2/M boundary. In addition, PARP3 inhibition potentiates vinorelbine interaction with tubulin. Furthermore, olaparib or ME0328 potentiates vinorelbine-induced PARP3 inhibition, mitotic arrest, and apoptosis.

Conclusion

Our results indicated this approach with PARP3 inhibitors and vinorelbine is unique and promising for breast cancer patients with metastases. This combination could significantly increase the survival of breast cancer patients with metastases.

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Funding

The Cancer Research Society supported this investigation. Grant Number: 01713.

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Authors and Affiliations

  1. Montreal Centre for Experimental Therapeutics in Cancer Segal Cancer Center, Lawrence Panasci & Raquel Aloyz Segal Cancer Center, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, 3755 Cote Ste Catherine, Montréal, QC, H3T 1E2, Canada

    Bahram Sharif-Askari, Lilian Amrein, Raquel Aloyz & Lawrence Panasci

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  1. Bahram Sharif-Askari
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  2. Lilian Amrein
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  3. Raquel Aloyz
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  4. Lawrence Panasci
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Correspondence to Raquel Aloyz or Lawrence Panasci.

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The authors declare that they have no conflict of interest.

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The experiments comply with the current laws of Canada in which they were performed.

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Sharif-Askari, B., Amrein, L., Aloyz, R. et al. PARP3 inhibitors ME0328 and olaparib potentiate vinorelbine sensitization in breast cancer cell lines. Breast Cancer Res Treat 172, 23–32 (2018). https://doi.org/10.1007/s10549-018-4888-6

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  • DOI: https://doi.org/10.1007/s10549-018-4888-6

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