Abstract
Cancer stem-like cells (CSCs) are the principal causes of tumor radio-resistance, dormancy and recurrence after radiotherapy. Clinical trials show hyperthermia (HT) might be a potent radiation sensitizer. In this study, CSCs were found to be more susceptible to radiation when combined with HT treatment. Treated cells showed significantly reduced self-renewal, cell survival and proliferation in vitro, as well as significant reduced tumor formation in vivo. Further study demonstrated that the radiosensitization effect was associated with increased intracellular reactive oxygen species (ROS) level in CSCs, confirmed by modifying redox status in CSCs bidirectionally. Pharmacologic depletion of glutathione by buthionine sulphoximine mimicked HT induced radiosensitivity in CSCs. Antioxidant N-acetylcysteine could efficiently rescue HT induced radiosensitivity in CSCs. To our knowledge, this may be the first report suggesting the association between elevated intracellular ROS level and HT induced radiosensitization in human breast CSCs and pancreatic CSCs, which might provide new strategy for improving CSCs radiosensitivity.
Highlights
Accumulating data have indicated the existence of cancer stem-like cells (CSCs) in multiple solid tumors [1,2,3]
The similar extent (29%) of reducing mammosphere growth was found in either ionizing radiation (IR)+buthionine sulphoximine (BSO) group or IR+HT group compared with IR group (59.2% ± 3.2% for IR+BSO and 59.6% ± 3.4% for IR+HT versus 89.0% ± 9.0% for IR, Figure 5F), Collectively, the results indicated that BSO mimicked HT induced radiosensitivity
Many Phase III clinical trials show the combination of HT with IR result in higher response rates, accompanied with improved local tumor control rates, better palliative effects, and/or better overall survival rates [34,35,36]
Summary
Accumulating data have indicated the existence of cancer stem-like cells (CSCs) in multiple solid tumors [1,2,3]. CSCs are a subset of tumor cells that have the ability to self-renewal and generate diverse tumor cells [2]. These cells are currently believed to be responsible for treatment failures because of their resistance to conventional treatments including ionizing radiation (IR) [4,5,6] and chemotherapy [7,8,9]. The effects produced by the sequence between IR and HT may vary with different tumor types, combination of IR and HT at the same time kills the most tumor cells [18,19]. As the time interval increases, the radiosensitization by heat could hardly be observed
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