Effect of olaparib in combination with doxorubicin on MDA-MB-231 breast cancer cell line

Mayra L Sottile¹,4, Analia L Redondo¹,4, Matilde de Paola2,4, Laura C Gomez¹, Marcelo de Campos-Nebel³, Laura M Vargas-Roig¹,4

Breast cancer (BC) is the leading cause of cancer death in women in Argentina. Anthracycline-based regimens represent the major chemotherapeutic agents used in BC treatment. However, chemotherapy resistance development and adverse effects are still a challenge for the oncology. Poly [ADP-ribose] polymerase (PARP) is a key DNA repair protein mainly involved in base excision repair. In the last years, PARP inhibitors (PARPi) have been approved for the treatment of BRCA-mutated BC. As PARP is involved in doxorubicin-induced cellular response, the aim of this work was to determine the effect of the PARPi olaparib on the sensitivity of BC cells to the anthracycline doxorubicin. MDA-MB-231 cells were treated with increasing concentrations of doxorubicin (5-40 nM), olaparib (1 µM) or doxorubicin and olaparib during 24 h. Clonogenic assay, viability assay and immunofluorescence were performed. Simultaneous administration of the drugs resulted in a combination index <1, which indicates a synergistic effect of doxorubicin and olaparib. In addition, the cell viability was significantly lower for cells exposed to combined treatment in MDA-MB-231 cell line. Residual DNA damage (evaluated by γH2AX foci) was higher for cells exposed to simultaneous treatment with respect to individual administration of the drugs. These preliminary results suggest that PARP inhibition may potentiate the effect of doxorubicin in BRCA-proficient breast cancer cells.