Extended multidrug resistance in haemopoietic cells

Area of Science:

• Hematology
• Molecular Biology
• Pharmacology

Background:

• Drug resistance is a major challenge in cancer chemotherapy.
• Understanding the mechanisms of multidrug resistance (MDR) is crucial for improving treatment efficacy.
• Haemopoietic cell lineage may influence the development of drug resistance.

Purpose of the Study:

• To investigate the relationship between cell lineage and the development of drug resistance in haemopoietic cells.
• To characterize the multidrug resistance (MDR) phenotype induced by chemotherapy agents in different cell lines.
• To explore the role of P-glycoprotein in acquired drug resistance in myeloid cell lines.

Main Methods:

• Treatment of U937 (monocytic) and HL60 (promyelocytic) cell lines with epirubicin and vinblastine.
• Assessment of cross-resistance to various chemotherapy drugs, including paclitaxel, etoposide, chlorambucil, cis-platinum, and methotrexate.
• Evaluation of P-glycoprotein expression and function using verapamil to assess drug accumulation.

Main Results:

• Induced sublines of U937 and HL60 cells exhibited an extended MDR phenotype with cross-resistance to multiple drug classes.
• Overexpression of P-glycoprotein was observed, but it appeared non-functional in U937 sublines as verapamil did not restore drug accumulation.
• KG1a and HEL cell lines showed functional P-glycoprotein and inherent resistance to treatment concentrations.

Conclusions:

• The development of an extended MDR phenotype in myeloid cells is influenced by cell lineage.
• P-glycoprotein-mediated resistance alone cannot fully explain chemotherapy resistance in chronic myeloid leukemia (CML) patients, particularly in blast crisis.
• Acquired MDR in myeloid cells may involve mechanisms independent of functional P-glycoprotein, contributing to treatment failure in CML.