Journal
BIOMOLECULES
Volume 12, Issue 11, Pages -Publisher
MDPI
DOI: 10.3390/biom12111623
Keywords
hepatocellular carcinoma; cancer stem cells; doxorubicin; autophagy; CD133; aptamer
Categories
Funding
- Indo-Australia Science and Technology Fund [ST040007]
- Victorian Cancer Agency Platform Technology Capacity Building Grant [PTCP-02]
- CASS Foundation (Australia)
- Deakin University Postgraduate Research Scholarship
Ask authors/readers for more resources
This study aimed to overcome drug resistance in liver cancer caused by cancer stem cells by using a CD133 aptamer for targeted delivery of Doxorubicin and enhancing the treatment efficacy through autophagy inhibition. The results showed that CD133 aptamer-guided delivery of Doxorubicin resulted in a higher concentration of Doxorubicin in liver cancer stem cells. The combinatorial treatment strategy of CD133 aptamer-Doxorubicin conjugates and an autophagy inhibitor showed a significantly higher elimination of liver cancer stem cells in vitro.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available