Tyrosine kinase inhibitors protect the salivary gland from radiation damage by increasing DNA double-strand break repair

Affandi, Trisiani; Ohm, Angela M.; Gaillard, David; Haas, Ami; Reyland, Mary E.

doi:10.1016/j.jbc.2021.100401

Cited by 15 publications

(12 citation statements)

References 63 publications

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“…To investigate of the biodistribution and SMG target of tFNAs, tFNAs (100 μl, 250 nΜ) was intravenously injected to normal rats and irradiated rats. Then, the rats were euthanized at different time points (15,45…”

Section: Biodistributionmentioning

confidence: 99%

“…11 Based on the severe situation, research on the treatment of irradiation-induced salivary gland damage has received extensive attention. [12][13][14][15] The occurrence of irradiation-induced salivary gland damage is a complex process involving many factors. In the early stage of radiotherapy, no obvious morphological changes were observed in the salivary glands.…”

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confidence: 99%

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Tetrahedral framework nucleic acids alleviate irradiation‐induced salivary gland damage

Xie

Guo

et al. 2022

Cell Proliferation

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In this study, we investigated the role of tetrahedral framework nucleic acids (tFNAs) in irradiation-induced salivary gland damage in vitro and in vivo. Irradiation-damaged submandibular gland cells (SMGCs) were treated with different concentrations of tFNAs. Cell activity was measured by CCK-8 assay. Cell death was detected by Calcein-AM/PI double staining. Cell apoptosis was assessed by flow cytometry. The expression of apoptosis proteins and inflammatory cytokines were detected by western blot. Body weight, drinking volume, saliva flow rate and lag time was measured 8 weeks after irradiation. Micromorphological changes of submandibular gland were assessed by haematoxylin-eosin and masson staining. Cell proliferation, apoptosis and microvessel density of submandibular gland were evaluated by immunohistochemical staining. tFNAs could promote cell proliferation, inhibit cell apoptosis of irradiation-damaged SMGCs and reduce irradiation induced cell death. Mechanism studies revealed that tFNAs inhibited cell apoptosis through regulating the Bcl-2/Bax/Caspase-3 signalling pathway and inhibited the release of TNF-α, IL-1β and IL-6 to reduce cell damage caused by inflammation. Animal experiments showed that tFNAs could alleviate irradiation-induced weight loss, increased water intake, decreased saliva production and prolonged salivation lag time and could ameliorate salivary gland damage. tFNAs have a positive effect on alleviating irradiation-induced salivary gland damage and might be a promising agent for the treatment of this disease. | INTRODUCTIONRadiotherapy is a vital treatment for head and neck cancer. Approximately 80% of patients suffering from head and neck cancer have received radiotherapy. However, radiotherapy can cause many Xueping Xie and Wenjuan Ma contribute equally to this work.

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Section: Biodistributionmentioning

confidence: 99%

mentioning

confidence: 99%

Tetrahedral framework nucleic acids alleviate irradiation‐induced salivary gland damage

Xie

Guo

et al. 2022

Cell Proliferation

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“…Moreover, TKIs increase the basal and IR-induced expression of genes associated with NHEJ (DNA ligase-4, Artemis, and XLF) and HR (Rad50, Rad51, and BRCA1). TKIs provide radioprotection to the salivary gland tissues and support the clinical exploration of TKIs in head and neck cancer patients undergoing IR therapy [ 129 ].…”

Section: Treatment Of Risgimentioning

confidence: 99%

Mechanism, Prevention, and Treatment of Radiation-Induced Salivary Gland Injury Related to Oxidative Stress

et al. 2021

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Radiation therapy is a common treatment for head and neck cancers. However, because of the presence of nerve structures (brain stem, spinal cord, and brachial plexus), salivary glands (SGs), mucous membranes, and swallowing muscles in the head and neck regions, radiotherapy inevitably causes damage to these normal tissues. Among them, SG injury is a serious adverse event, and its clinical manifestations include changes in taste, difficulty chewing and swallowing, oral infections, and dental caries. These clinical symptoms seriously reduce a patient’s quality of life. Therefore, it is important to clarify the mechanism of SG injury caused by radiotherapy. Although the mechanism of radiation-induced SG injury has not yet been determined, recent studies have shown that the mechanisms of calcium signaling, microvascular injury, cellular senescence, and apoptosis are closely related to oxidative stress. In this article, we review the mechanism by which radiotherapy causes oxidative stress and damages the SGs. In addition, we discuss effective methods to prevent and treat radiation-induced SG damage.

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“…However, there are data on the genotoxicity of selected TKIs to human cells in vitro and mainly to targeted cancer cell lines. Several in vitro studies have confirmed that DAS [ 56 , 57 ] and REG [ 58 , 59 ] induce DNA damage assessed by comet assay in certain target cancer cells. In contrast to our results, the European Medicines Agency (EMEA) reported that NIL did not induce DNA single-strand breaks in the mouse L5178Y cell line evaluated by the comet assay [ 60 ].…”

Section: Resultsmentioning

confidence: 99%

Adverse Toxic Effects of Tyrosine Kinase Inhibitors on Non-Target Zebrafish Liver (ZFL) Cells

Kološa

Žegura

Štampar

et al. 2023

IJMS

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Over the past 20 years, numerous tyrosine kinase inhibitors (TKIs) have been introduced for targeted therapy of various types of malignancies. Due to frequent and increasing use, leading to eventual excretion with body fluids, their residues have been found in hospital and household wastewaters as well as surface water. However, the effects of TKI residues in the environment on aquatic organisms are poorly described. In the present study, we investigated the cytotoxic and genotoxic effects of five selected TKIs, namely erlotinib (ERL), dasatinib (DAS), nilotinib (NIL), regorafenib (REG), and sorafenib (SOR), using the in vitro zebrafish liver cell (ZFL) model. Cytotoxicity was determined using the MTS assay and propidium iodide (PI) live/dead staining by flow cytometry. DAS, SOR, and REG decreased ZFL cell viability dose- and time-dependently, with DAS being the most cytotoxic TKI studied. ERL and NIL did not affect viability at concentrations up to their maximum solubility; however, NIL was the only TKI that significantly decreased the proportion of PI negative cells as determined by the flow cytometry. Cell cycle progression analyses showed that DAS, ERL, REG, and SOR caused the cell cycle arrest of ZFL cells in the G0/G1 phase, with a concomitant decrease of cells in the S-phase fraction. No data could be obtained for NIL due to severe DNA fragmentation. The genotoxic activity of the investigated TKIs was evaluated using comet and cytokinesis block micronucleus (CBMN) assays. The dose-dependent induction of DNA single strand breaks was induced by NIL (≥2 μM), DAS (≥0.006 μM), and REG (≥0.8 μM), with DAS being the most potent. None of the TKIs studied induced micronuclei formation. These results suggest that normal non-target fish liver cells are sensitive to the TKIs studied in a concentration range similar to those previously reported for human cancer cell lines. Although the TKI concentrations that induced adverse effects in exposed ZFL cells are several orders of magnitude higher than those currently expected in the aquatic environment, the observed DNA damage and cell cycle effects suggest that residues of TKIs in the environment may pose a hazard to non-intentionally exposed organisms living in environments contaminated with TKIs.

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Tyrosine kinase inhibitors protect the salivary gland from radiation damage by increasing DNA double-strand break repair

Cited by 15 publications

References 63 publications

Tetrahedral framework nucleic acids alleviate irradiation‐induced salivary gland damage

Tetrahedral framework nucleic acids alleviate irradiation‐induced salivary gland damage

Mechanism, Prevention, and Treatment of Radiation-Induced Salivary Gland Injury Related to Oxidative Stress

Adverse Toxic Effects of Tyrosine Kinase Inhibitors on Non-Target Zebrafish Liver (ZFL) Cells

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