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Targeting ABCB1 (MDR1) in multi-drug resistant osteosarcoma cells using the CRISPR-Cas9 system to reverse drug
Tang Liu1,2, Zhihong Li1, Qing Zhang1
1Department of Orthopaedics, The 2nd Xiangya Hospital of Central South University, Changsha, Hunan, 410011, P.R. China.
Background:
Multi-drug resistance (MDR) remains a significant obstacle to successful chemotherapy treatment for osteosarcoma patients. One of the central causes of MDR is the overexpression of the membrane bound drug transporter protein P-glycoprotein (P-gp), which is the protein product of the MDR gene ABCB1. Though several methods have been reported to reverse MDR in vitro and in vivo when combined with anticancer drugs, they have yet to be proven useful in the clinical setting.
Results:
The meta-analysis demonstrated that a high level of P-gp may predict poor survival in patients with osteosarcoma. The expression of P-gp can be efficiently blocked by the clustered regularly interspaced short palindromic repeats (CRISPR)-associated Cas9 system (CRISPR-Cas9). Inhibition of ABCB1 was associated with reversing drug resistance in osteosarcoma MDR cell lines (KHOSR2 and U-2OSR2) to doxorubicin.
Materials And Methods:
We performed a meta-analysis to investigate the relationship between P-gp expression and survival in patients with osteosarcoma. Then we adopted the CRISPR-Cas9, a robust and highly efficient novel genome editing tool, to determine its effect on reversing drug resistance by targeting endogenous ABCB1 gene at the DNA level in osteosarcoma MDR cell lines.
Conclusion:
These results suggest that the CRISPR-Cas9 system is a useful tool for the modification of ABCB1 gene, and may be useful in extending the long-term efficacy of chemotherapy by overcoming P-gp-mediated MDR in the clinical setting.
Insights
Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing effectively reverses multidrug resistance (MDR) in osteosarcoma by targeting the ABCB1 gene. This approach shows promise for improving chemotherapy efficacy in patients with P-glycoprotein-mediated MDR.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Multidrug resistance (MDR) is a major challenge in osteosarcoma chemotherapy.
- Overexpression of P-glycoprotein (P-gp), encoded by the ABCB1 gene, is a primary cause of MDR.
- Current MDR reversal methods lack clinical translation.
Purpose of the Study:
- To investigate the link between P-gp expression and osteosarcoma patient survival.
- To evaluate the efficacy of CRISPR-Cas9 in reversing drug resistance in osteosarcoma.
Main Methods:
- Meta-analysis of P-gp expression and osteosarcoma survival data.
- Utilized CRISPR-Cas9 genome editing to target the ABCB1 gene in osteosarcoma MDR cell lines.
- Assessed the impact of ABCB1 inhibition on doxorubicin resistance.
Main Results:
- High P-gp expression correlates with poor survival in osteosarcoma patients.
- CRISPR-Cas9 efficiently blocks P-gp expression.
- Inhibition of ABCB1 reversed doxorubicin resistance in osteosarcoma cell lines.
Conclusions:
- CRISPR-Cas9 is effective for modifying the ABCB1 gene.
- This gene editing system holds potential for overcoming P-gp-mediated MDR.
- CRISPR-Cas9 may enhance long-term chemotherapy efficacy in clinical settings.
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