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ABCB1-overexpressing MG63/DOX cell xenograft model: maintain the MDR phenotype in vivo
Zhiyong Zhou1, Lili Wan, Yonglong Han
1Department of Pharmacy, Affiliated Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, China.
Context:
Multi-drug resistance (MDR) constitutes a major obstacle in the effectiveness of chemotherapy. P-Glycoprotein (P-gp), the product of ABCB1 gene, is a transmembrane transporter that actively pumps cytotoxic drugs out of tumor cells resulting in MDR.
Objective:
We sought to establish an MG63/DOX cell xenografts model that maintained the MDR phenotype and molecular properties in vivo in order to screen for new P-gp inhibitors.
Materials And Methods:
The cytotoxicities of doxorubicin, paclitaxel and cytarabine were evaluated by MTT assays. P-gp activity was measured by rhodamine 123 accumulation using flow cytometry. P-gp expression in MG63/DOX cells and tumor tissues was detected by western blotting and immunohistochemistry.
Results:
Our results showed that MG63/DOX cells exhibited 70-fold resistance to doxorubicin and more than 150-fold resistance to paclitaxel compared with parent MG63 cells. Furthermore, the ABCB1 inhibitor verapamil (10 μM) effectively reversed doxorubicin and paclitaxel resistance by 90- and 200-fold, respectively. The intracellular accumulation of rhodamine 123 was significantly increased (8.35-fold) in MG63/DOX cell, as compared to MG63 cells, in the presence of 10 μM verapamil. MG63/DOX tumor chunk xenografts had a high formation rate (88%). Finally, we found that the ABCB1 gene was overexpressed in different generations of solid tumors.
Discussion And Conclusion:
These data demonstrated that MG63/DOX tumor chunk subculture in vivo retained their molecular properties. This model could serve as a convenient system for the preclinical investigation of drug combinations and the screening of new agents to reverse ABCB1-mediated MDR.
Insights
A new in vivo model using MG63/DOX cells effectively mimics multi-drug resistance (MDR) by overexpressing P-glycoprotein (P-gp). This model aids in screening new agents to overcome chemotherapy resistance.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Multi-drug resistance (MDR) is a significant challenge in chemotherapy effectiveness.
- P-glycoprotein (P-gp), encoded by the ABCB1 gene, actively expels drugs from tumor cells, causing MDR.
Purpose of the Study:
- To establish an MG63/DOX cell xenograft model that preserves MDR phenotype and molecular characteristics in vivo.
- To utilize this model for screening novel P-gp inhibitors.
Main Methods:
- MTT assays to determine cytotoxicity of doxorubicin, paclitaxel, and cytarabine.
- Flow cytometry to measure P-gp activity via rhodamine 123 accumulation.
- Western blotting and immunohistochemistry to detect P-gp expression in cells and tumor tissues.
Main Results:
- MG63/DOX cells showed 70-fold resistance to doxorubicin and >150-fold to paclitaxel compared to parent cells.
- Verapamil, an ABCB1 inhibitor, reversed resistance by 90-fold (doxorubicin) and 200-fold (paclitaxel).
- MG63/DOX xenografts exhibited high formation rate (88%) with sustained ABCB1 overexpression.
Conclusions:
- The MG63/DOX tumor xenograft model retains its molecular properties in vivo.
- This model is suitable for preclinical evaluation of drug combinations and screening for agents targeting ABCB1-mediated MDR.
