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.
Highlights
This article is an open access articleAbout 50% of cancer patients undergo radiotherapy during the course of their treatment either for curative prospect or palliative assistance [1]
Our results propose a new therapeutic approach combining protons or X-rays and Olaparib with senolytic agents to decrease the number of senescent cells, enhancing cell death and reducing the risk of treatment failure
The induction of senescence was investigated in A549 cells exposed to irradiation with or without these different drugs
Summary
About 50% of cancer patients undergo radiotherapy during the course of their treatment either for curative prospect or palliative assistance [1]. In order to improve patient outcome, treatments usually combine surgery, chemotherapy and radiotherapy. Amongst the strategies to optimize cell response distributed under the terms and conditions of the Creative Commons. The improvement of dose spatial distribution aims at dose escalation, hypofractionation and the sparing of healthy tissues. Techniques such as intensity modulated radiation therapy (IMRT) must be favored as well as stereotactic body radiotherapy (SBRT), which is being pushed forward. In the seeking of dose conformation, charged particles, such as protons or carbon ions, present a clear advantage compared to photons due to their depth dose profile [5,6]. While photons deposit most of their energy close to the surface entrance, followed by a continuous decrease characteristic in their attenuation, charged particles deposit a small fraction of their energy before what is called the Bragg peak
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