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 autopha...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(H_(2)O_(2))to disintegrate into CO and Mn^(2+).The comprehensive effect of CO/Mn^(2+)and CBD can induce ROS-mediated cell apoptosis.In addition,HMPOC@Mmediated excessive autophagy can promote cancer cell death by increasing autophagic flux via classⅢPI3K/BECN1 complex activation and blocking autolysosome degradation via LAMP1 downregulation.Furthermore,in vivo 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.展开更多
基金partially supported by the Natural Science Foundation of Hunan Province(2020JJ4005,2020JJ5421,2021JJ30096,China)National Natural Science Funds of China(82003931)+3 种基金The China Postdoctoral Science Foundation(2021M690974,China)Agricultural Science and Technology Innovation Project of Chinese Academy of Agricultural Sciences(CAAS-ASTIP-IBFC04,China)Opening foundation of Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province(2022CG01,China)Key Research and Development Projects in Ningxia Autonomous Region(2022BFH02013,China)。
文摘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(H_(2)O_(2))to disintegrate into CO and Mn^(2+).The comprehensive effect of CO/Mn^(2+)and CBD can induce ROS-mediated cell apoptosis.In addition,HMPOC@Mmediated excessive autophagy can promote cancer cell death by increasing autophagic flux via classⅢPI3K/BECN1 complex activation and blocking autolysosome degradation via LAMP1 downregulation.Furthermore,in vivo 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.
