Taking Advantage of the Senescence-Promoting Effect of Olaparib after X-ray and Proton Irradiation Using the Senolytic Drug, ABT-263.

Abstract

Simple SummaryRadiotherapy is one of the most common treatments for cancer. Overcoming the failure and side effects of radiotherapy are current challenges. It has been recently demonstrated that senescence contributes to radioresistance. Cellular senescence is a permanent arrest in cell proliferation induced by various factors, such as radiation. Here, we aimed to assess the potential of combining the radiation and DNA damage repair inhibitor, Olaparib to a senolytic drug, ABT-263. We demonstrated that combining radiation, Olaparib and ABT-263 successfully targeted the radio-induced senescent cells resulting in increased cell death and reduced senescence-associated secretory phenotype. These results paved the way towards a new therapeutic combination for patients treated with radiotherapy and Olaparib.Radiotherapy (RT) is a key component of cancer treatment. Although improvements have been made over the years, radioresistance remains a challenge. For this reason, a better understanding of cell fates in response to RT could improve therapeutic options to enhance cell death and reduce adverse effects. Here, we showed that combining RT (photons and protons) to noncytotoxic concentration of PARP inhibitor, Olaparib, induced a cell line-dependent senescence-like phenotype. The senescent cells were characterized by morphological changes, an increase in p21 mRNA expression as well as an increase in senescence-associated β-galactosidase activity. We demonstrated that these senescent cells could be specifically targeted by Navitoclax (ABT-263), a Bcl-2 family inhibitor. This senolytic drug led to significant cell death when combined with RT and Olaparib, while limited cytotoxicity was observed when used alone. These results demonstrate that a combination of RT with PARP inhibition and senolytics could be a promising therapeutic approach for cancer patients.