1α,25(OH)2D3 Radiosensitizes Cancer Cells by Activating the NADPH/ROS Pathway

Abstract

The radioresistance of tumors affect the outcome of radiotherapy. Accumulating data suggest that 1a,25(OH) 2 D 3 is a potential anti-oncogenic molecule in various cancers. In the present study, we investigated the radiosensitive effects and underlying mechanisms of 1a,25(OH) 2 D 3 in vitro and in vivo. We found that 1a,25(OH) 2 D 3 enhanced the radiosensitivity of lung cancer and ovarian cancer cells by promoting the NADPH oxidase-ROS-apoptosis axis. Compared to the group that only received radiation, the survival fraction and selfrenewal capacity of cancer cells treated with a combination of 1a,25(OH) 2 D 3 and radiation were decreased. Both apoptosis and ROS were significantly increased in the combination group compared with the radiation only group. Moreover, N-acetyl-L-cysteine, a scavenger of intracellular ROS, reversed the apoptosis and ROS induced by 1a,25(OH) 2 D 3 , indicating that 1a,25(OH) 2 D 3 enhanced the radiosensitivity of cancer cells in vitro by promoting ROSinduced apoptosis. Moreover, our results demonstrated that 1a,25(OH) 2 D 3 promoted the ROS level via activating NADPH oxidase complexes, NOX4, p22 phox , and p47 phox. In addition, knockdown of the vitamin D receptor (VDR) abolished the radiosensitization of 1a,25(OH) 2 D 3 , which confirmed that 1a,25(OH) 2 D 3 radiosensitized tumor cells that depend on VDR. Similarly, our study also evidenced that vitamin D 3 enhanced the radiosensitivity of cancer cells in vivo and extended the overall survival of mice with tumors. In summary, these results demonstrate that 1a,25(OH) 2 D 3 enhances the radiosensitivity depending on VDR and activates the NADPH oxidase-ROS-apoptosis axis. Our findings suggest that 1a,25 (OH) 2 D 3 in combination with radiation enhances lung and ovarian cell radiosensitivity, potentially providing a novel combination therapeutic strategy.

The Effectiveness of Vitamin D Supplementation on Oxidative and Inflammatory Markers in Patients Suffering from End-stage Renal Disease, a Randomized Controlled Trial

“…In addition, our results showed that the severity of oxidative damage is associated directly with the severity of vitamin D deficiency and treatment with this vitamin can significantly inhibit this damage. In agreement with these results, Ji et al, (2020) and Chen et al, (2019) showed that vitamin D supplementation through various cellular pathways could improve oxidative damage (28,29). These studies showed that the expression of Nrf2 was upregulated by vitamin D. Our results also showed that vitamin D supplementation could significantly improve serum levels of ALP and albumin.…”

Nuclear and Radiological Emergencies: Biological Effects, Countermeasures and Biodosimetry

“…Therefore, oral supplementation with vitamin D during radiotherapy or in professionals chronically exposed to low IR doses could be doubly useful, preventing radioinduced oxidative stress and osteoporosis [ 207 ]. Recent studies evidence that calcitriol selectively radiosensitizes cancer cells by activating the NADPH/ROS pathway [ 208 ].…”

Radioprotectors, Radiomitigators, and Radiosensitizers

“…Therefore, oral supplementation with vitamin D during RT or in medical professionals chronically exposed to low IR doses should be taken into consideration also because radiation toxicity can reduce mineral bone density. Recent studies evidence that calcitriol also radiosensitizes cancer cells by activating the NADPH/ROS pathway, which can makes it a promising adjuvant in RT [80].…”