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

摘要 据估计，2021年美国有45，230人被诊断患有直肠癌。直肠癌 主要通过化疗、放疗和手术的组合来治疗。手术切除 直肠与长期功能缺陷和生活质量下降有关。因此， 改善对新辅助放化疗反应可以提高非手术治愈率， 直肠癌患者的生活质量。一氧化碳（CO）在低，无毒浓度已被证明 提供矛盾的抗肿瘤作用，同时抑制炎症和氧化应激诱导的正常组织 损伤，可以作为辅助治疗，以提高化疗-放疗的疗效。CO是以下物质的产物 由Nrf 2转录因子和细胞保护基因血红素加氧酶-1（HO-1）调节的血红素催化剂 1）。一氧化碳同时致敏肿瘤细胞死亡的生化机制 正常细胞存活是未知的，但可能涉及氧化代谢的根本差异， 癌细胞和正常细胞确定直肠中CO活性的靶向氧化还原敏感机制 癌症可能会迅速导致转化治疗方法，以改善癌症的辐射反应 同时限制正常组织损伤。我们已经开发了令人兴奋的新方法，通过CO输送， 胃肠道（GI）以克服吸入CO的挑战。使用这些GI制剂递送CO， 我们的中心假设是，一氧化碳作为一种安全的生物泡沫，选择性地使直肠化学-放射增敏， 癌症，同时减少正常组织损伤。此外，该机制涉及对以下方面的不同影响： Nrf 2/HO-1信号传导和线粒体氧化代谢的调节。我们将评估 细胞保护性CO生物泡沫对暴露后正常直肠组织反应和氧化损伤的影响 在小鼠中测定CO作为直肠癌治疗的辅助的效果。

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.