Engineering cannabidiol synergistic carbon monoxide nanocomplexes to enhance cancer therapy via excessive autophagy

Chang Xiao; Yue Sun; Jialong Fan; William Nguyen; Simin Chen; Ying Long; Wei Chen; Aiguo Zhu; Bin Liu

doi:10.1016/j.apsb.2023.05.019

Engineering cannabidiol synergistic carbon monoxide nanocomplexes to enhance cancer therapy via excessive autophagy

Acta Pharm Sin B. 2023 Nov;13(11):4591-4606. doi: 10.1016/j.apsb.2023.05.019. Epub 2023 May 29.

Authors

Chang Xiao¹, Yue Sun^{1

2}, Jialong Fan¹, William Nguyen³, Simin Chen¹, Ying Long¹, Wei Chen³, Aiguo Zhu⁴, Bin Liu¹

Affiliations

¹ College of Biology, Hunan University, Changsha 410082, China.
² General Hospital of Ningxia Medical University, School of Public Health and Management, Ningxia Medical University, Yinchuan 750004, China.
³ Department of Physics, the University of Texas at Arlington, Arlington, TX 76019, USA.
⁴ Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha 410205, China.

Abstract

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 (H₂O₂) to disintegrate into CO and Mn²⁺. The comprehensive effect of CO/Mn²⁺ and CBD can induce ROS-mediated cell apoptosis. In addition, HMPOC@M-mediated excessive autophagy can promote cancer cell death by increasing autophagic flux via class III PI3K/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.

Keywords: Autolysosome degradation; Autophagic flux; Cannabidiol; Carbon monoxide therapy; Excessive autophagy; Metastases; Reactive oxygen species; Triple-negative breast cancer.