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Inhibition of Autophagy Promotes the Elimination of Liver Cancer Stem Cells by CD133 Aptamer-Targeted Delivery of Doxorubicin
journal contributionposted on 2023-02-03, 04:57 authored by W Yin, CV Pham, T Wang, H Al Shamaileh, R Chowdhury, S Patel, Y Li, Lingxue KongLingxue Kong, Y Hou, Y Zhu, S Chen, H Xu, L Jia, Wei DuanWei Duan, D Xiang
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.
Publication classificationC1 Refereed article in a scholarly journal
AFFINITYANTIBODYaptamerautophagyBiochemistry & Molecular Biologycancer stem cellsCD133doxorubicinhepatocellular carcinomaLife Sciences & BiomedicineScience & TechnologyHumansCarcinoma, HepatocellularDoxorubicinNeoplastic Stem CellsAutophagyLiver NeoplasmsCell Line, TumorRegenerative MedicineLiver DiseaseCancerDigestive DiseasesRare DiseasesLiver CancerStem Cell ResearchBiotechnologyOrphan Drug5 Development of treatments and therapeutic interventions5.1 PharmaceuticalsBiochemistry and Cell Biology not elsewhere classified