Xiao Chang, Sun Yue, Fan Jialong, Nguyen William, Chen Simin, Long Ying, Chen Wei, Zhu Aiguo, Liu Bin
College of Biology, Hunan University, Changsha 410082, China.
General Hospital of Ningxia Medical University, School of Public Health and Management, Ningxia Medical University, Yinchuan 750004, China.
Acta Pharm Sin B. 2023 Nov;13(11):4591-4606. doi: 10.1016/j.apsb.2023.05.019. Epub 2023 May 29.
Although carbon monoxide (CO)-based treatments have demonstrated the high cancer efficacy by promoting mitochondrial damage and core-region penetrating ability, the efficiency was often compromised by protective autophagy (mitophagy). Herein, cannabidiol (CBD) is integrated into biomimetic carbon monoxide nanocomplexes (HMPOC@M) to address this issue by inducing excessive autophagy. The biomimetic membrane not only prevents premature drugs leakage, but also prolongs blood circulation for tumor enrichment. After entering the acidic tumor microenvironment, carbon monoxide (CO) donors are stimulated by hydrogen oxide (HO) to disintegrate into CO and Mn. The comprehensive effect of CO/Mn and CBD can induce ROS-mediated cell apoptosis. In addition, HMPOC@M-mediated excessive autophagy can promote cancer cell death by increasing autophagic flux class III PI3K/BECN1 complex activation and blocking autolysosome degradation LAMP1 downregulation. Furthermore, experiments showed that HMPOC@M+ laser strongly inhibited tumor growth and attenuated liver and lung metastases by downregulating VEGF and MMP9 proteins. This strategy may highlight the pro-death role of excessive autophagy in TNBC treatment, providing a novel yet versatile avenue to enhance the efficacy of CO treatments. Importantly, this work also indicated the applicability of CBD for triple-negative breast cancer (TNBC) therapy through excessive autophagy.
尽管基于一氧化碳（CO）的治疗方法已通过促进线粒体损伤和核心区域穿透能力展现出较高的抗癌疗效，但该疗效常因保护性自噬（线粒体自噬）而受到影响。在此，将大麻二酚（CBD）整合到仿生一氧化碳纳米复合物（HMPOC@M）中，通过诱导过度自噬来解决这一问题。仿生膜不仅可防止药物过早泄漏，还能延长血液循环以实现肿瘤富集。进入酸性肿瘤微环境后，一氧化碳（CO）供体受过氧化氢（HO）刺激分解为CO和Mn。CO/Mn与CBD的综合作用可诱导活性氧介导的细胞凋亡。此外，HMPOC@M介导的过度自噬可通过增加自噬通量（III类磷脂酰肌醇3激酶/BECN1复合物激活）和阻断自溶酶体降解（溶酶体相关膜蛋白1下调）来促进癌细胞死亡。此外，实验表明，HMPOC@M +激光通过下调血管内皮生长因子（VEGF）和基质金属蛋白酶9（MMP9）蛋白，强烈抑制肿瘤生长并减轻肝肺转移。该策略可能凸显过度自噬在三阴性乳腺癌（TNBC）治疗中的促死亡作用，为提高CO治疗疗效提供了一条新颖且通用的途径。重要的是，这项工作还表明CBD通过过度自噬对三阴性乳腺癌（TNBC）治疗具有适用性。
