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Establishment and characterization of arsenic trioxide resistant KB/ATO cells
Yun-Kai Zhang1, Chunling Dai1,2, Chun-Gang Yuan3
1Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John׳s University, Queens, NY 11439, USA.
Abstract:
Arsenic trioxide (ATO) is used as a chemotherapeutic agent for the treatment of acute promyelocytic leukemia. However, increasing drug resistance is reducing its efficacy. Therefore, a better understanding of ATO resistance mechanism is required. In this study, we established an ATO-resistant human epidermoid carcinoma cell line, KB/ATO, from its parental KB-3-1 cells. In addition to ATO, KB/ATO cells also exhibited cross-resistance to other anticancer drugs such as cisplatin, antimony potassium tartrate, and 6-mercaptopurine. The arsenic accumulation in KB/ATO cells was significantly lower than that in KB-3-1 cells. Further analysis indicated that neither application of P-glycoprotein inhibitor, breast cancer resistant protein (BCRP) inhibitor, or multidrug resistance protein 1 (MRP1) inhibitor could eliminate ATO resistance. We found that the expression level of ABCB6 was increased in KB/ATO cells. In conclusion, ABCB6 could be an important factor for ATO resistance in KB/ATO cells. The ABCB6 level may serve as a predictive biomarker for the effectiveness of ATO therapy.
Insights
Arsenic trioxide (ATO) resistance in cancer cells is a growing problem. Researchers identified increased ABCB6 expression as a key factor in ATO resistance, suggesting it could predict treatment effectiveness.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Arsenic trioxide (ATO) is a crucial chemotherapy for acute promyelocytic leukemia.
- Increasing ATO drug resistance necessitates understanding its underlying mechanisms.
- This study investigates the molecular basis of ATO resistance in cancer cells.
Purpose of the Study:
- To establish and characterize an ATO-resistant cancer cell line.
- To identify the mechanisms contributing to ATO resistance.
- To explore potential biomarkers for predicting ATO therapy efficacy.
Main Methods:
- Established an ATO-resistant cell line (KB/ATO) from parental KB-3-1 cells.
- Assessed cross-resistance to various anticancer drugs.
- Quantified arsenic accumulation in resistant vs. sensitive cells.
- Evaluated the impact of P-glycoprotein, BCRP, and MRP1 inhibitors.
- Analyzed the expression levels of ABCB6 in both cell lines.
Main Results:
- KB/ATO cells displayed cross-resistance to multiple chemotherapeutic agents.
- Arsenic accumulation was significantly reduced in KB/ATO cells compared to KB-3-1 cells.
- Inhibitors of P-glycoprotein, BCRP, and MRP1 did not reverse ATO resistance.
- A notable increase in ABCB6 expression was observed in KB/ATO cells.
Conclusions:
- ABCB6 is identified as a significant contributor to ATO resistance in the established KB/ATO cell line.
- Elevated ABCB6 levels may serve as a predictive biomarker for ATO treatment outcomes.
- Further research into ABCB6's role can guide the development of strategies to overcome ATO resistance.
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