Targeting ABCB1 (MDR1) in multi-drug resistant osteosarcoma cells using the CRISPR-Cas9 system to reverse drug resistance.

Abstract

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.

• Authors: Tang Liu, Zhihong Li, Qing Zhang, Karen De Amorim Bernstein, Santiago Lozano-Calderon, Edwin Choy, Francis J Hornicek, Zhenfeng Duan
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 50 Pg. 83502-83513 (Dec 13 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27835872 (Publication Type: Journal Article, Meta-Analysis, Review)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• Antibiotics, Antineoplastic
• Doxorubicin

Topics

• ATP Binding Cassette Transporter, Subfamily B (genetics, metabolism)
• Antibiotics, Antineoplastic (pharmacology)
• Bone Neoplasms (drug therapy, genetics, metabolism, pathology)
• CRISPR-Cas Systems
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Doxorubicin (pharmacology)
• Drug Resistance, Multiple (genetics)
• Drug Resistance, Neoplasm (genetics)
• Gene Editing (methods)
• Gene Expression Regulation, Neoplastic
• Humans
• Osteosarcoma (drug therapy, genetics, metabolism, pathology)
• Transfection