Exploiting Carbon Monoxide Biofoams to Radio-Sensitize Rectal Cancer Cells While Protecting Normal Bowel

摘要 据估计，2021年美国有45230人被诊断患有直肠癌。直肠癌 主要使用化疗、放射治疗和手术相结合的方法进行治疗。外科手术切除眼球 直肠与长期的功能缺陷和生活质量下降有关。因此，应采取以下策略 改善对新辅助放化疗的反应可以提高非手术治愈率和 直肠癌患者的生活质量。一氧化碳(CO)已被证明在低浓度、无毒 在抑制炎症和氧化应激诱导的正常组织的同时提供矛盾的抗肿瘤作用 可作为辅助治疗以提高放化疗疗效的损伤。CO是一种产品 Nrf2转录因子和细胞保护基因HO-1对血红素分解代谢的调节 1)。一氧化碳使肿瘤细胞在保存的同时敏化死亡的生化机制 正常的细胞存活尚不清楚，但可能涉及氧化代谢的根本差异 癌症和正常细胞。确定直肠一氧化碳活性的靶向氧化还原敏感机制 癌症可以迅速带来改善癌症放射反应的转化性治疗方法 同时限制正常组织损伤。我们已经开发出令人振奋的新方法，通过 胃肠道(GI)克服吸入一氧化碳的挑战。使用这些GI配方来输送CO， 我们的中心假设是，CO作为一种安全的生物泡沫输送，选择性地使直肠具有化学-放射敏感性 癌症的同时减少对正常组织的损伤。此外，该机制涉及对 NRF2/HO-1信号转导与线粒体氧化代谢的调控我们将评估这些措施的影响 细胞保护性CO生物泡沫暴露后对正常直肠组织反应和氧化损伤的影响 化疗和放射治疗，并确定一氧化碳作为治疗直肠癌的辅助治疗小鼠的效果。

ABSTRACT An estimated 45,230 individuals were diagnosed with rectal cancer in the United States in 2021. Rectal cancer is primarily managed using a combination of chemotherapy, radiation, and surgery. Surgical resection of the rectum is associated with long-term functional deficits and decreased quality-of-life. Therefore, strategies to improve response to neoadjuvant chemoradiotherapy could increase non-surgical curative rates and enhance quality-of-life for rectal cancer patients. Carbon monoxide (CO) at low, non-toxic concentrations has been shown to provide paradoxical anti-tumor effects while inhibiting inflammation and oxidative-stress induced normal tissue injury that could serve as an adjuvant treatment to enhance chemo-radiotherapy efficacy. CO is a product of heme catabolism regulated by the Nrf2 transcription factor and the cytoprotective gene Heme Oxygenase-1 (HO- 1). The biochemical mechanisms by which CO simultaneously sensitizes tumor cells to die while preserving normal cell survival are unknown but likely involve fundamental differences in oxidative metabolism between cancer and normal cells. Identifying targetable redox sensitive mechanisms underlying the activity of CO in rectal cancer could rapidly lead to translational therapeutic approaches for improving radiation responses in cancers while limiting normal tissue injury. We have developed exciting new methods for CO delivery through the gastrointestinal (GI) tract to overcome the challenges of inhaled CO. Using these GI formulations to deliver CO, our central hypothesis is that CO, delivered as a safe biofoam, selectively chemo-radio-sensitizes rectal cancer while reducing normal tissue injury. Further that the mechanism involves differential effects on Nrf2/HO-1 signaling and modulation of mitochondrial oxidative metabolism. We will evaluate the impact of cytoprotective CO biofoams on normal rectal tissue responses and oxidative damage after exposure to chemoradiotherapy and determine the effects of CO as an adjunct to therapy for rectal cancer in mice.