Mechanism, Prevention, and Treatment of Radiation-Induced Salivary Gland Injury Related to Oxidative Stress
Abstract
:1. Introduction
2. Mechanism of RISGI
3. Calcium Signaling
4. Microvascular Injury
5. Decreased Parasympathetic Nerve Signals
6. Water Channel Hypothesis
7. Cellular Senescence and Apoptosis
8. Treatment of RISGI
8.1. Amifostine
8.2. Antioxidant Stress Therapy
8.3. Growth Factor Therapy
8.4. Molecular Targeted Therapy
8.4.1. Targeted TGF-β Therapy
8.4.2. Targeted PKCδ Therapy
8.4.3. Targeting PI3K/AKT/mTOR Pathway
8.5. Stem Cell Therapy
8.5.1. Save SCs to Reduce IR Damage
8.5.2. Other Functioning SCs
8.6. Gene Transfer Therapy
Transferred Genes
9. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Treatment | Radiation Dose | Medicine | Drug Dosage | Mode of Administration | Routes of Administration | Mechanism | Conclusion | Reference |
---|---|---|---|---|---|---|---|---|
IGF1 | 5 Gy | Roscovitine | 25 mg/kg 100 mg/kg | Intraperitoneal injection | Female FVB mice | A cyclin-dependent kinase inhibitor that acts to transiently inhibit cell cycle progression and allow for DNA repair in damaged tissues. | Induction of transient G2/M cell cycle arrest by roscovitine allows for the suppression of apoptosis, thus preserving normal salivary function following targeted head and neck irradiation. | [123] |
5 Gy | IGF1 | 5 μg/mouse | Tail-vein injection | FVB, C57BL/6 J, and Prkcz−/− mice | Administration of IGF1 post-radiation maintains the activation of aPKCζ and partially rescues Yap’s cellular localization in label-retaining cells while restoring salivary function. | aPKCζ is required to restore the function of irradiated SGs using IGF1. This restoration process involves the maintenance of aPKCζ phosphorylation and the modulation of nuclear translocation of Yap in acinar LRCs in an aPKCζ-dependent fashion. | [125] | |
2 or 5 Gy | IGF1 | 10 ng/mL | Intravenous injection | Human UMSCC1, UMSCC23, CAL 27, A-253, and FaDU cells | Not stated | Head and neck squamous carcinoma cell xenografts treated with concurrent radiation and IGF1 also exhibit significant tumor growth delay. | [124] | |
5 Gy | IGF1 | 5 μg | Vehicle injection | Female FVB mice | Not stated | Post-therapeutic IGF1 treatment restores SG function, potentially through the normalization of cell proliferation and the improved expression of amylase. | [16] | |
5 Gy | Intravenous recombinant human IGF1 | 5 μg | Intravenous | FVB females | In parotid glands of irradiated mice pretreated with IGF1, reduced ΔNp63 protein facilitates a p53-mediated increase in p21 expression that leads to G2/M arrest. | Radiation-induced increases in ΔNp63 protein correspond with enhanced binding to the p21 promoter and decreased p21 transcription in irradiated parotid glands after 8 h compared to parotid glands pretreated with IGF1. | [122] | |
Targeted therapy | 15 Gy | HBOT | Once a day for five consecutive days a week | - | Female C3H mice | Not stated | HBOT can inhibit the TGFβ-pathway in irradiated SGs and restrain consequential radiation-induced tissue injury. | [127] |
15 Gy | SIM | 10 mg/kg | IP injection | Male ICR mice | The protective benefits of SIM may be attributed to scavenging malondialdehyde, remitting collagen deposition, and reducing and delaying the elevation of TGFβ1 expression induced by radiation. | SIM remitted the reduction of saliva secretion and restored salivary amylase activity. | [126] | |
10 or 15 Gy | Imatinib dasatinib | Imatinib (50 mg/kg) and dasatinib (20 mg/kg) | Not stated | The ParC5 cell line HNSCC cell lines | PKCδ is required for IR-induced apoptosis in the SG and that blocking activation of PKCδ with TKIs suppresses apoptosis. | Dasatinib and imatinib provide the profound and durable protection of SG function in vivo when delivered in conjunction with a single or fractionated doses of IR. | [128] | |
Not stated | Imatinib dasatinib | Dasatinib (20 mg/kg) | Not stated | ParC5 cell line 293T cells | TKIs effective against c-Src and c-Abl are able to block multiple key regulatory steps necessary for PKCδ nuclear localization, leading to suppression of apoptosis both in vitro and in vivo. | TKIs is useful for the protection of nontumor tissues in patients undergoing radiotherapy of the head and neck. | [63] |
Study | Cells | Radiation Dose | Treatment | Detection Method | Pathway to Restore SG Function | Treatment Effect | Conclusion | Reference |
---|---|---|---|---|---|---|---|---|
Martti Maimets et al. | SG ductal EpCAM and cells | 15 Gy | - | SFR | Wnt signals | Nuclear β-catenin. | Stimulating self-renewal and long-term expansion of SG organoids, containing all differentiated SG cell types. | [136] |
Bo Hai et al. | Mouse SGs and cultured human salivary epithelial cells | 15 Gy | Sonic hedgehog (Shh) transgene or Smoothened Agonist in mouse salivary glands, adenovirus encoding Gli1 in human salivary epithelial cells | Detection of Ptch1-lacZ reporter gene and endogenous Hedgehog target gene expression | Transient activation of Hedgehog pathway | Preservation of salivary stem/progenitor cells, the Bmi1 signaling pathway, parasympathetic innervation, Chrm1/HB-EGF signaling, and expression of neurotrophic factors after IR by transient Hh activation. | Transient Shh overexpression activated the Hedgehog pathway in ductal epithelia, thus rescuing salivary function in male mice, which was related to the preservation of functional SSPCs and parasympathetic innervation. | [131] |
Yoshinori Sumita et al. | Salivary epithelial cells | 18 Gy | BMDCs | The expression of stem cell markers (Sca-1 or c-kit) | Direct differentiation of donor BMDCs into salivary epithelial cells | An increased ratio of acinar-cell area and approximately 9% of Y-chromosome-positive (donor-derived) salivary epithelial cells in BMDC-treated mice. | A cell-therapy approach, the transplantation of BMDCs via intravenous injections, can regenerate radiation-damaged tissue and rescue SG functions. | [150] |
Xiaohong Peng et al. | SG sphere derived cells of Gdnf hypermorphic (Gdnfwt/hyper) and wild type mice (Gdnfwt/wt) | 0, 1, 2, 4, and 8 Gy | - | QPCR and immunofluorescence | GDNF–RET signaling pathway | MSGSC of Gdnfwt/hyper mice showed high sphere-forming efficiency upon replating. | GDNF does not protect mSGSCs against irradiation but seems to promote mSGSC proliferation through the GDNF–RET signaling pathway. | [134] |
Julie P Saiki et al. | Adult WT and Aldh3a1−/− murine SMGs | 15 and 30 Gy | D-limonene | PAS staining annexin V PI | ALDH3A1 plays an important role in protecting SSPCs from IR-induced injury by increasing aldehyde scavenging. | ALDH3A1 activation with d-Limonene reduces aldehydic load, improves sphere growth, and reduces apoptosis in SMGs. | d-limonene may be a good clinical candidate for mitigating xerostomia in patients with head and neck cancer receiving radiation therapy. | [145] |
Nan Xiao et al. | C57BL/6 mice C57BL/6-Tg(UBC-GFP)30Scha/J mice | 15 Gy |
Lin–CD24+ c-Kit+Sca1+ stem cells (GDNF) | PAS staining revealed more functional and intact acini in GDNF-treated SMGs than in saline glands | Not stated | Administration of GDNF improved saliva production and enriched the number of functional acini in submandibular glands of irradiated animals, as well as enhancing salisphere formation in cultured salivary stem cells, but it did not accelerate growth of head and neck cancer cells. | GDNF pathway may have potential therapeutic benefit for the management of radiation-induced xerostomia. | [135] |
Bo Hai et al. | C57BL/6 mice | 15 Gy | Adenoviral vector encoding GFP or rat Shh | Detection of SA-β-gal activity | mRNA levels of Chek1, Egfr, and survivin were significantly upregulated by the transfer of Shh inhibition of GDF15 upregulation | Shh gene transfer represses IR-induced cellular senescence by promoting DNA repair, decreasing oxidative stress (which is mediated through upregulating expression of genes related to DNA repair such as survivin and miR-21), and repressing expression of the pro-senescence gene Gdf15 likely downstream of miR-21. | Repressing cellular senescence contributes to the rescue of IR-induced hyposalivation by the transient activation of Hh signaling, which is related to enhanced DNA repair and decreased oxidative stress in SMGs. | [7] |
Junye Zhang et al. | C57BL/6 mice | 18 Gy | DFO | SFR | DFO improved angiogenesis via activating HIF–1α–VEGF Pathway | In addition to the restoration of salivary function, DFO administration also increased angiogenesis and the number of stem/progenitor cells while reducing the apoptosis of acinar cells. | DFO could prevent the radiation-induced dysfunction of SGs in mice. | [133] |
Scheme | Radiation Dose | Vector | Gene | Model | Detection Method | Pathway | Treatment Effect | Conclusion | Reference |
---|---|---|---|---|---|---|---|---|---|
Runtao Gao et al. | 20 Gy | Serotype 2 and AAV2 vector | hAQP1 cDNA | Salivary hypofunction in minipigs | SFR | Not stated | In glands treated with the AAV2hAQP1 vector, a steady increase in parotid SFR was seen, such that by week 8, they were on average 35% of pre-IR values—nearly 1 mL/10 min. | The AAV2hAQP1 vector could be useful for targeting IR-surviving duct cells in previously irradiated head and neck cancer patients and providing them with a more extended (months) means of increasing salivary flow versus the AdhAQP1 vector (days). | [151] |
C Zheng et al. | Not stated | hCMVp | hAQP1 cDNA | Female C3H mice and male Wistar rats | PCR assays Measurement of cell volume | Not stated | Not stated | The hCMVp in AdhAQP1was probably not methylated in transduced human SG cells of responding subjects, resulting in an unexpectedly longer functional expression of hAQP1. | [154] |
L Guo et al. | 7.5 or 9 Gy | Hybrid serotype 5 adenoviral vector | FGF2 cDNA | Parotid glands of minipigs | Local blood flow rate measurement | Not stated | Compared to the IR and AdLacZ and IR groups, the salivary flow rates of the AdLTR2EF1α-FGF2 and IR group were significantly higher (p < 0.001) and only slightly changed from that of naive animals. | Pre-administration of AdLTR2EF1α-FGF2 prevented an IR-induced reduction in MVD in minipig parotid glands within 24 h after IR. Pre-administration of AdLTR2EF1α-FGF2 also led to significantly higher levels of salivary secretion than those seen with untreated but irradiated minipigs and with minipigs that were irradiated and administered a control vector. | [118] |
Chang yu Zheng et al. | 15 Gy | AdLTR2EF1α-hKGF | KGF | Female C3H mice | Salivary flow | Not stated | The SFR from 2 groups (Mice receiving 15 Gy and AdControl) were also significantly lower than those of irradiated mice treated with AdLTR2EF1α-hKGF (p < 0.001). In contrast, the salivary flow rates from the no-IR and AdLTR2EF1α-hKGF plus IR groups were not significantly different (p = 0.065). | The hKGF gene transfer had no effect on the growth or radiation sensitivity of a model SCC. Transfer of the hKGF gene to SGs prior to both fractionated and single-dose IR substantially prevents salivary hypofunction. | [119] |
Bo Hai et al. | 15 Gy | Adenoviral vector | Shh delivery | B6;129-Ptch1tm1Mps/J (Ptch1-lacZ) mice and wild-type C57BL/6 mice | X-Gal staining and qRT-PCR analysis saliva flow rate | Hedgehog/Gli | Shh gene transfer is a feasible approach to restore SG function after radiotherapy, which functions through ameliorations of IR damage to the microvasculature and parasympathetic innervation by the upregulation of paracrine factors. | Transient activation of the Hedgehog pathway by gene delivery is promising to rescue salivary function after irradiation in both sexes. | [159] |
Liang Hu et al. | 20 Gy | Adenoviral vector | GFP or Shh | Healthy littermate BA–MA male miniature pigs | IHC qRT-PCR analysis | Hedgehog/Gli | Shh gene delivery 4 weeks after irradiation significantly improved stimulated saliva secretion and local blood supply up to 20 weeks; preserved saliva-producing acinar cells, parasympathetic innervation and microvessels as found in mouse models; and activated autophagy and inhibited fibrogenesis in irradiated glands. | The translational potential of transient activation of the Hedgehog pathway to preserve salivary function following irradiation. | [155] |
Bo Hai et al. | 15 Gy | Adenoviral vector | human Gli1 or GFP | Ptch1-lacZ mice | qRT-PCR analysis and X-gal staining | Hedgehog/Gli | Transient Shh overexpression activated the Hedgehog pathway in ductal epithelia; and this, after irradiation, rescued salivary function in male mice, which was related to the preservation of functional SSPCs and parasympathetic innervation. | Transient activation of the Hedgehog pathway has the potential to restore irradiation-induced SG dysfunction. | [131] |
Bo Hai et al. | Not stated | Serotype 2 AAV2 vectors | hEpo | Miniature pig | Enzyme-linked immunosorbent assay | - | AAV2 vectors mediate extended gene transfer to miniature pig parotid glands and should be useful for testing pre-clinical gene therapy strategies aiming to correct SG radiation damage. | AAV2 vectors mediate extended gene transfer to miniature pig parotid glands and should be useful for testing pre-clinical gene therapy strategies aiming to correct SG radiation damage. | [163] |
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Liu, Z.; Dong, L.; Zheng, Z.; Liu, S.; Gong, S.; Meng, L.; Xin, Y.; Jiang, X. Mechanism, Prevention, and Treatment of Radiation-Induced Salivary Gland Injury Related to Oxidative Stress. Antioxidants 2021, 10, 1666. https://doi.org/10.3390/antiox10111666
Liu Z, Dong L, Zheng Z, Liu S, Gong S, Meng L, Xin Y, Jiang X. Mechanism, Prevention, and Treatment of Radiation-Induced Salivary Gland Injury Related to Oxidative Stress. Antioxidants. 2021; 10(11):1666. https://doi.org/10.3390/antiox10111666
Chicago/Turabian StyleLiu, Zijing, Lihua Dong, Zhuangzhuang Zheng, Shiyu Liu, Shouliang Gong, Lingbin Meng, Ying Xin, and Xin Jiang. 2021. "Mechanism, Prevention, and Treatment of Radiation-Induced Salivary Gland Injury Related to Oxidative Stress" Antioxidants 10, no. 11: 1666. https://doi.org/10.3390/antiox10111666