Abstract
Simple SummaryDespite 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.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.
Highlights
Cancer is currently the leading cause of premature death between the ages of 30 and 69 years in Canada, the US, Australia, and most countries in Europe, including France, Germany, and the United Kingdom [1]
We show that these cells could be targeted by the use of zinc oxide nanoparticles (ZnO NPs)
In order to investigate the effects of gamma-irradiation on the cellular level, in v3iotrfo21 cultures of the tumor cell lines A549 and HuH-7 were treated with 16 Gy and studied with respect to cell death, cell cycle acrarercsitn, aonmda)pwroelirfeetrraetaiotendaws withel1l6asGmy oanrpdhsotluodgiiecdalwchitahrraecstpereicsttitcos.cell death, cell cycle arrest, and proliferation as well as morphological characteristics. 2.1
Summary
Cancer is currently the leading cause of premature death between the ages of 30 and 69 years in Canada, the US, Australia, and most countries in Europe, including France, Germany, and the United Kingdom [1]. Despite recent advancements in tumor therapy, metastasis and local recurrence are major hurdles to completely curing cancer. Local recurrence adversely affects both long-term survival and patient quality of life in several malignancies [2]. Local control of the tumor is essential to prevent recurrences and inhibit the migration of tumor cells leading to distant metastases [2]. Between 50% and 90% of cancer deaths are caused by metastases, underscoring the importance of the complete local control of the primary tumor and detection of the cancer as early as possible [3]
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