Zaher Amira, Mapuskar Kranti A, Petronek Michael S, Tanas Munir R, Isaacson Alexandra L, Dodd Rebecca D, Milhem Mohammed, Furqan Muhammad, Spitz Douglas R, Miller Benjamin J, Beardsley Robert A, Allen Bryan G
Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA.
Department of Pathology, The University of Iowa, Iowa City, IA 52242, USA.
Antioxidants (Basel). 2024 May 10;13(5):587. doi: 10.3390/antiox13050587.
Soft tissue sarcomas (STSs) are mesenchymal malignant lesions that develop in soft tissues. Despite current treatments, including radiation therapy (RT) and surgery, STSs can be associated with poor patient outcomes and metastatic recurrences. Neoadjuvant radiation therapy (nRT), while effective, is often accompanied by severe postoperative wound healing complications due to damage to the surrounding normal tissues. Thus, there is a need to develop therapeutic approaches to reduce nRT toxicities. Avasopasem manganese (AVA) is a selective superoxide dismutase mimetic that protects against IR-induced oral mucositis and lung fibrosis. We tested the efficacy of AVA in enhancing RT in STSs and in promoting wound healing. Using colony formation assays and alkaline comet assays, we report that AVA selectively enhanced the STS (liposarcoma, fibrosarcoma, leiomyosarcoma, and MPNST) cellular response to radiation compared to normal dermal fibroblasts (NDFs). AVA is believed to selectively enhance radiation therapy by targeting differential hydrogen peroxide clearance in tumor cells compared to non-malignant cells. STS cells demonstrated increased catalase protein levels and activity compared to normal fibroblasts. Additionally, NDFs showed significantly higher levels of GPx1 activity compared to STSs. The depletion of glutathione using buthionine sulfoximine (BSO) sensitized the NDF cells to AVA, suggesting that GPx1 may, in part, facilitate the selective toxicity of AVA. Finally, AVA significantly accelerated wound closure in a murine model of wound healing post RT. Our data suggest that AVA may be a promising combination strategy for nRT therapy in STSs.
软组织肉瘤（STSs）是发生于软组织的间充质恶性病变。尽管目前有包括放射治疗（RT）和手术在内的治疗方法，但STSs仍可能导致患者预后不良和转移性复发。新辅助放射治疗（nRT）虽然有效，但由于对周围正常组织的损伤，术后常伴有严重的伤口愈合并发症。因此，需要开发治疗方法以降低nRT的毒性。阿伐索泮锰（AVA）是一种选择性超氧化物歧化酶模拟物，可预防辐射诱导的口腔黏膜炎和肺纤维化。我们测试了AVA在增强STSs放疗效果和促进伤口愈合方面的功效。通过集落形成试验和碱性彗星试验，我们发现与正常真皮成纤维细胞（NDFs）相比，AVA能选择性增强STSs（脂肪肉瘤、纤维肉瘤、平滑肌肉瘤和恶性外周神经鞘膜瘤）细胞对辐射的反应。据信，与非恶性细胞相比，AVA通过靶向肿瘤细胞中不同的过氧化氢清除来选择性增强放射治疗效果。与正常成纤维细胞相比，STSs细胞的过氧化氢酶蛋白水平和活性增加。此外，与STSs相比，NDFs的谷胱甘肽过氧化物酶1（GPx1）活性水平显著更高。使用丁硫氨酸亚砜胺（BSO）消耗谷胱甘肽使NDF细胞对AVA敏感，这表明GPx1可能在一定程度上促进了AVA的选择性毒性。最后，在RT后的伤口愈合小鼠模型中，AVA显著加速了伤口闭合。我们的数据表明，AVA可能是STSs中nRT治疗的一种有前景的联合策略。
