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Inhibition of Autophagy Promotes the Elimination of Liver Cancer Stem Cells by CD133 Aptamer-Targeted Delivery of Doxorubicin

Wang YinIMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC 3216, AustraliaCuong Viet PhamIMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC 3216, AustraliaTao WangThe College of Nursing and Health, Zhengzhou University, Zhengzhou 450001, ChinaHadi Al ShamailehInstitute for Immunology and Infectious Diseases, Murdoch University, Perth, WA 6150, AustraliaRocky ChowdhuryIMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC 3216, AustraliaShweta PatelIMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC 3216, AustraliaYong LiSt George HospitalLingxue KongInstitute for Frontier Materials, Deakin University, Waurn Ponds, VIC 3216, AustraliaYingchu HouLaboratory of Tumor Molecular and Cellular Biology College of Life Sciences, Shaanxi Normal University, 620 West Chang’an Avenue, Xi’an 710119, ChinaYimin ZhuSuzhou Institute of Nano-tech and Nano-bionicsSunrui ChenHuo XuCollege of Materials and Chemical Engineering, Minjiang University, Fuzhou 350108, ChinaLee JiaCollege of Materials and Chemical Engineering, Minjiang University, Fuzhou 350108, ChinaWei DuanIMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC 3216, AustraliaDongxi XiangShanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200092, China

2022en

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Annotatsiya

Doxorubicin is the most frequently used chemotherapeutic agent for the treatment of hepatocellular carcinoma. However, one major obstacle to the effective management of liver cancer is the drug resistance derived from the cancer stem cells. Herein, we employed a CD133 aptamer for targeted delivery of doxorubicin into liver cancer stem cells to overcome chemoresistance. Furthermore, we explored the efficacy of autophagy inhibition to sensitize liver cancer stem cells to the treatment of CD133 aptamer-doxorubicin conjugates based on the previous observation that doxorubicin contributes to the survival of liver cancer stem cells by activating autophagy. The kinetics and thermodynamics of aptamer-doxorubicin binding, autophagy induction, cell apoptosis, and self-renewal of liver cancer stem cells were studied using isothermal titration calorimetry, Western blot analysis, annexin V assay, and tumorsphere formation assay. The aptamer-cell binding andintracellular accumulation of doxorubicin were quantified via flow cytometry. CD133 aptamer-guided delivery of doxorubicin resulted in a higher doxorubicin concentration in the liver cancer stem cells. The combinatorial treatment strategy of CD133 aptamer-doxorubicin conjugates and an autophagy inhibitor led to an over 10-fold higher elimination of liver cancer stem cells than that of free doxorubicin in vitro. Future exploration of cancer stem cell-targeted delivery of doxorubicin in conjunction with autophagy inhibition in vivo may well lead to improved outcomes in the treatment of hepatocellular carcinoma.

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DOI: 10.3390/biom12111623

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