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Current Drug Delivery

Editor-in-Chief

ISSN (Print): 1567-2018
ISSN (Online): 1875-5704

Research Article

Local Multiple-site Injections of a Plasmid Encoding Human MnSOD Mitigate Radiation-induced Skin Injury by Inhibiting Ferroptosis

Author(s): Xiaoying Wang, Yuxin Lu, Xiaochen Cheng, Xuefeng Zhu, Dujuan Li, Haiying Duan, Shenhui Hu, Fengjun Xiao, Li Du* and Qinglin Zhang*

Volume 21, Issue 5, 2024

Published on: 09 June, 2023

Page: [763 - 774] Pages: 12

DOI: 10.2174/1567201820666230508120720

Price: $65

Abstract

Background: Most patients who undergo radiotherapy develop radiation skin injury, for which effective treatment is urgently needed. MnSOD defends against reactive oxygen species (ROS) damage and may be valuable for treating radiation-induced injury. Here, we (i) investigated the therapeutic and preventive effects of local multiple-site injections of a plasmid, encoding human MnSOD, on radiation-induced skin injury in rats and (ii) explored the mechanism underlying the protective effects of pMnSOD.

Methods: The recombinant plasmid (pMnSOD) was constructed with human cytomegalovirus (CMV) promoter and pUC-ori. The protective effects of pMnSOD against 20-Gy X-ray irradiation were evaluated in human keratinocytes (HaCaT cells) by determining cell viability, ROS levels, and ferroptosisrelated gene expression. In therapeutic treatment, rats received local multiple-site injections of pMnSOD on days 12, 19, and 21 after 40-Gy γ-ray irradiation. In preventive treatment, rats received pMnSOD injections on day -3 pre-irradiation and on day 4 post-irradiation. The skin injuries were evaluated based on the injury score and pathological examination, and ferroptosis-related gene expression was determined.

Results: In irradiated HaCaT cells, pMnSOD transfection resulted in an increased SOD2 expression, reduced intracellular ROS levels, and increased cell viability. Moreover, GPX4 and SLC7A11 expression was significantly upregulated, and erastin-induced ferroptosis was inhibited in HaCaT cells. In the therapeutic and prevention treatment experiments, pMnSOD administration produced local SOD protein expression and evidently promoted the healing of radiation-induced skin injury. In the therapeutic treatment experiments, the injury score in the high-dose pMnSOD group was significantly lower than in the PBS group on day 33 post-irradiation (1.50 vs. 2.80, P < 0.05). In the prevention treatment experiments, the skin injury scores were much lower in the pMnSOD administration groups than in the PBS group from day 21 to day 34. GPX4, SLC7A11, and Bcl-2 were upregulated in irradiated skin tissues after pMnSOD treatment, while ACSL4 was downregulated.

Conclusion: The present study provides evidence that the protective effects of MnSOD in irradiated HaCaT cells may be related to the inhibition of ferroptosis. The multi-site injections of pMnSOD had clear therapeutic and preventive effects on radiation-induced skin injury in rats. pMnSOD may have therapeutic value for the treatment of radiation-induced skin injury.

Keywords: Radiation-induced skin injury, manganese superoxide dismutase (MnSOD), gene therapy, ferroptosis, ROS, CMV.

Graphical Abstract
[1]
Urbański, B. The future of radiation oncology: Considerations of young medical doctor. Rep. Pract. Oncol. Radiother., 2012, 17(5), 288-293.
[http://dx.doi.org/10.1016/j.rpor.2012.09.002] [PMID: 24669310]
[2]
Ryan, J.L. Ionizing radiation: The good, the bad, and the ugly. J. Invest. Dermatol., 2012, 132(3), 985-993.
[http://dx.doi.org/10.1038/jid.2011.411] [PMID: 22217743]
[3]
Jia, H.; Mo, W.; Hong, M.; Jiang, S.; Zhang, Y.Y.; He, D.; Yu, D.; Shi, Y.; Cao, J.; Xu, X.; Zhang, S. Interferon-α inducible protein 6 (IFI6) confers protection against ionizing radiation in skin cells. J. Dermatol. Sci., 2020, 100(2), 139-147.
[http://dx.doi.org/10.1016/j.jdermsci.2020.09.003] [PMID: 33059972]
[4]
Kim, J.H.; Kolozsvary, A.J.J.; Jenrow, K.A.; Brown, S.L. Mechanisms of radiation-induced skin injury and implications for future clinical trials. Int. J. Radiat. Biol., 2013, 89(5), 311-318.
[http://dx.doi.org/10.3109/09553002.2013.765055] [PMID: 23305180]
[5]
Soriano, J.L.; Calpena, A.C.; Souto, E.B.; Clares, B. Therapy for prevention and treatment of skin ionizing radiation damage: A review. Int. J. Radiat. Biol., 2019, 95(5), 537-553.
[http://dx.doi.org/10.1080/09553002.2019.1562254] [PMID: 30570420]
[6]
Maurine Wickline, M. Prevention and treatment of acute radiation dermatitis: A literature review. Oncol. Nurs. Forum, 2004, 31(2), 237-247.
[http://dx.doi.org/10.1188/04.ONF.237-247] [PMID: 15017440]
[7]
Pinnix, C.; Perkins, G.H.; Strom, E.A.; Tereffe, W.; Woodward, W.; Oh, J.L.; Arriaga, L.; Munsell, M.F.; Kelly, P.; Hoffman, K.E.; Smith, B.D.; Buchholz, T.A.; Yu, T.K. Topical hyaluronic acid vs. standard of care for the prevention of radiation dermatitis after adjuvant radiotherapy for breast cancer: single-blind randomized phase III clinical trial. Int. J. Radiat. Oncol. Biol. Phys., 2012, 83(4), 1089-1094.
[http://dx.doi.org/10.1016/j.ijrobp.2011.09.021] [PMID: 22172912]
[8]
Koukourakis, G.; Pissakas, G.; Ganos, C.G.; Sivolapenko, G.; Kardamakis, D. Effectiveness and tolerability of natural herbal formulations in the prevention of radiation-induced skin toxicity in patients undergoing radiotherapy. Int. J. Low. Extrem. Wounds, 2022, 21(1), 75-86.
[http://dx.doi.org/10.1177/1534734620923912] [PMID: 32525718]
[9]
Huayllani, M.T.; Ruiz-Garcia, H.; Boczar, D.; Avila, F.R.; Lu, X.; Rinker, B.D.; Moran, S.L.; Sarabia-Estrada, R.; Quiñones-Hinojosa, A.; Forte, A.J. Adipose-derived stem cells therapy for radiation-induced skin injury. Ann. Plast. Surg., 2021, 87(6), 639-649.
[http://dx.doi.org/10.1097/SAP.0000000000003039] [PMID: 34724441]
[10]
Baidoo, K.E. Yong, K Molecular pathways: Targeted α-particle radiation therapy. Clin. Cancer Res., 2013, 19(3), 530-537.
[11]
Yang, P.; Luo, X.; Li, J.; Zhang, T.; Gao, X.; Hua, J.; Li, Y.; Ding, N.; He, J.; Zhang, Y.; Wei, W.; Wang, J.; Zhou, H. Ionizing radiation upregulates glutamine metabolism and induces cell death via accumulation of reactive oxygen species. Oxid. Med. Cell. Longev., 2021, 2021, 1-22.
[http://dx.doi.org/10.1155/2021/5826932] [PMID: 35028001]
[12]
Lei, G.; Mao, C.; Yan, Y.; Zhuang, L.; Gan, B. Ferroptosis, radiotherapy, and combination therapeutic strategies. Protein Cell, 2021, 12(11), 836-857.
[http://dx.doi.org/10.1007/s13238-021-00841-y] [PMID: 33891303]
[13]
Zelko, I.N.; Mariani, T.J.; Folz, R.J. Superoxide dismutase multigene family: A comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic. Biol. Med., 2002, 33(3), 337-349.
[14]
Bonetta, R. Potential therapeutic applications of MnSODs and SOD-Mimetics. Chemistry, 2018, 24(20), 5032-5041.
[http://dx.doi.org/10.1002/chem.201704561] [PMID: 29131419]
[15]
Averbeck, D.; Rodriguez-Lafrasse, C. Role of mitochondria in radiation responses: Epigenetic, metabolic, and signaling impacts. Int. J. Mol. Sci., 2021, 22(20), 11047.
[http://dx.doi.org/10.3390/ijms222011047] [PMID: 34681703]
[16]
Epperly, M.; Bray, J.; Kraeger, S.; Zwacka, R.; Engelhardt, J.; Travis, E.; Greenberger, J. Prevention of late effects of irradiation lung damage by manganese superoxide dismutase gene therapy. Gene Ther., 1998, 5(2), 196-208.
[http://dx.doi.org/10.1038/sj.gt.3300580] [PMID: 9578839]
[17]
Stickle, R.L.; Epperly, M.W.; Klein, E.; Bray, J.A.; Greenberger, J.S. Prevention of irradiation-induced esophagitis by plasmid/liposome delivery of the human manganese superoxide dismutase transgene. Radiat. Oncol. Investig., 1999, 7(4), 204-217.
[http://dx.doi.org/10.1002/(SICI)1520-6823(1999)7:4<204:AID-ROI2>3.0.CO;2-S] [PMID: 10492161]
[18]
Guo, H.; Seixas-Silva, J.A., Jr; Epperly, M.W.; Gretton, J.E.; Shin, D.M.; Bar-Sagi, D.; Archer, H.; Greenberger, J.S. Prevention of radiation-induced oral cavity mucositis by plasmid/liposome delivery of the human manganese superoxide dismutase (SOD2) transgene. Radiat. Res., 2003, 159(3), 361-370.
[http://dx.doi.org/10.1667/0033-7587(2003)159[0361:PORIOC]2.0.CO;2] [PMID: 12600239]
[19]
Kanai, A.J.; Zeidel, M.L.; Lavelle, J.P.; Greenberger, J.S.; Birder, L.A.; De Groat, W.C.; Apodaca, G.L.; Meyers, S.A.; Ramage, R.; Epperly, M.W. Manganese superoxide dismutase gene therapy protects against irradiation-induced cystitis. Am. J. Physiol. Renal Physiol., 2002, 283(6), F1304-F1312.
[http://dx.doi.org/10.1152/ajprenal.00228.2002] [PMID: 12426235]
[20]
Everett, W.H.; Curiel, D.T. Gene therapy for radioprotection. Cancer Gene Ther., 2015, 22(4), 172-180.
[http://dx.doi.org/10.1038/cgt.2015.8] [PMID: 25721205]
[21]
Hu, C.; Cheng, X.; Lu, Y.; Wu, Z.; Zhang, Q. Gram-scale production of plasmid pUDK-HGF with current good manufacturing practices for gene therapy of critical limb ischemia. Prep. Biochem. Biotechnol., 2016, 46(8), 844-849.
[http://dx.doi.org/10.1080/10826068.2016.1141302] [PMID: 26853514]
[22]
Kulshrestha, S.; Chawla, R.; Singh, S.; Yadav, P.; Sharma, N.; Goel, R. Protection of sildenafil citrate hydrogel against radiation-induced skin wounds. Burns, 2020, 46(5), 1157-1169.
[http://dx.doi.org/10.1016/j.burns.2019.11.020]
[23]
Wolff, J.A.; Budker, V. The mechanism of naked DNA uptake and expression. Adv. Genet., 2005, 54, 1-20.
[http://dx.doi.org/10.1016/S0065-2660(05)54001-X] [PMID: 16096005]
[24]
Jiao, Y.; Cao, F.; Liu, H. Radiation-induced cell death and its mechanisms. Health Phys., 2022, 123(5), 376-386.
[http://dx.doi.org/10.1097/HP.0000000000001601] [PMID: 36069830]
[25]
Yang, Y.; Jiang, G.; Zhang, P.; Fan, J. Programmed cell death and its role in inflammation. Mil. Med. Res., 2015, 2(1), 12.
[http://dx.doi.org/10.1186/s40779-015-0039-0] [PMID: 26045969]
[26]
Lei, G.; Zhang, Y.; Koppula, P.; Liu, X.; Zhang, J.; Lin, S.H.; Ajani, J.A.; Xiao, Q.; Liao, Z.; Wang, H.; Gan, B. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res., 2020, 30(2), 146-162.
[http://dx.doi.org/10.1038/s41422-019-0263-3] [PMID: 31949285]
[27]
Bonetta Valentino, R. The structure–function relationships and physiological roles of MnSOD mutants. Biosci. Rep., 2022, 42(6)BSR20220202
[http://dx.doi.org/10.1042/BSR20220202] [PMID: 35662317]
[28]
Stockwell, B.R.; Friedmann Angeli, J.P.; Bayir, H.; Bush, A.I.; Conrad, M.; Dixon, S.J.; Fulda, S.; Gascón, S.; Hatzios, S.K.; Kagan, V.E.; Noel, K.; Jiang, X.; Linkermann, A.; Murphy, M.E.; Overholtzer, M.; Oyagi, A.; Pagnussat, G.C.; Park, J.; Ran, Q.; Rosenfeld, C.S.; Salnikow, K.; Tang, D.; Torti, F.M.; Torti, S.V.; Toyokuni, S.; Woerpel, K.A.; Zhang, D.D. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell, 2017, 171(2), 273-285.
[http://dx.doi.org/10.1016/j.cell.2017.09.021] [PMID: 28985560]
[29]
Liu, T.; Jiang, L.; Tavana, O.; Gu, W. The deubiquitylase OTUB1 mediates ferroptosis via stabilization of SLC7A11. Cancer Res., 2019, 79(8), 1913-1924.
[http://dx.doi.org/10.1158/0008-5472.CAN-18-3037] [PMID: 30709928]
[30]
Lang, X.; Green, M.D.; Wang, W.; Yu, J.; Choi, J.E.; Jiang, L.; Liao, P.; Zhou, J.; Zhang, Q.; Dow, A.; Saripalli, A.L.; Kryczek, I.; Wei, S.; Szeliga, W.; Vatan, L.; Stone, E.M.; Georgiou, G.; Cieslik, M.; Wahl, D.R.; Morgan, M.A.; Chinnaiyan, A.M.; Lawrence, T.S.; Zou, W. Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Discov., 2019, 9(12), 1673-1685.
[http://dx.doi.org/10.1158/2159-8290.CD-19-0338] [PMID: 31554642]
[31]
Feng, Z.; Qin, Y.; Huo, F.; Jian, Z.; Li, X.; Geng, J.; Li, Y.; Wu, J. NMN recruits GSH to enhance GPX4-mediated ferroptosis defense in UV irradiation induced skin injury. Biochim. Biophys. Acta Mol. Basis Dis., 2022, 1868(1)166287
[http://dx.doi.org/10.1016/j.bbadis.2021.166287] [PMID: 34626772]
[32]
Doll, S.; Proneth, B.; Tyurina, Y.Y.; Panzilius, E.; Kobayashi, S.; Ingold, I.; Irmler, M.; Beckers, J.; Aichler, M.; Walch, A.; Prokisch, H.; Trümbach, D.; Mao, G.; Qu, F.; Bayir, H.; Füllekrug, J.; Scheel, C.H.; Wurst, W.; Schick, J.A.; Kagan, V.E.; Angeli, J.P.F.; Conrad, M. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol., 2017, 13(1), 91-98.
[http://dx.doi.org/10.1038/nchembio.2239] [PMID: 27842070]
[33]
Zhang, Y.; Li, S.; Li, F.; Lv, C. High-fat diet impairs ferroptosis and promotes cancer invasiveness via downregulating tumor suppressor ACSL4 in lung adenocarcinoma. Biol. Direct, 2021, 16(1), 10.

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