Zinc Oxide Nanoparticles Can Intervene in Radiation-Induced Senescence and Eradicate Residual Tumor Cells

SIMPLE SUMMARY: Despite great advancements in modern cancer therapy, many patients suffer from local recurrence after initial treatment. The phenomenon of regrowth of tumor cells after several months or years is increasingly connected to therapy-induced cellular senescence. Our goal was to investigate the properties of tumor cells after survival of 16 Gy gamma-irradiation. We revealed the classical hallmarks of senescence among the remnant cell mass after irradiation. Furthermore, the observed radiation-induced senescence was associated with the increased ability to withstand further irradiation and cells were shown to possess the ability to regrow within several weeks. Moreover, treatment with zinc oxide nanoparticles proved to be an attractive therapeutic option to eradicate the residual senescent tumor cells. ABSTRACT: Despite recent advancements in tumor therapy, metastasis and tumor relapse remain major complications hindering the complete recovery of many cancer patients. Dormant tumor cells, which reside in the body, possess the ability to re-enter the cell cycle after therapy. This phenomenon has been attributed to therapy-induced senescence. We show that these cells could be targeted by the use of zinc oxide nanoparticles (ZnO NPs). In the present study, the properties of tumor cells after survival of 16 Gy gamma-irradiation were investigated in detail. Analysis of morphological features, proliferation, cell cycle distribution, and protein expression revealed classical hallmarks of senescent cells among the remnant cell mass after irradiation. The observed radiation-induced senescence was associated with the increased ability to withstand further irradiation. Additionally, tumor cells were able to re-enter the cell cycle and proliferate again after weeks. Treatment with ZnO NPs was evaluated as a therapeutical approach to target senescent cells. ZnO NPs were suitable to induce cell death in senescent, irradiation-resistant tumor cells. Our findings underline the pathophysiological relevance of remnant tumor cells that survived first-line radiotherapy. Additionally, we highlight the therapeutic potential of ZnO NPs for targeting senescent tumor cells.