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Immunotoxin resistance in multidrug resistant cells.
Melissa S McGrath1, Michael G Rosenblum, Mark R Philips
1Department of Immunology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York 10021, USA.
Cancer Research
|January 9, 2003
Summary
Multidrug resistance in cancer cells can be overcome by targeting P-glycoprotein (P-gp) mediated lysosomal degradation. This study shows increased lysosomal degradation of immunotoxins in P-gp expressing cells, suggesting a new therapeutic strategy.
Area of Science:
- Biochemistry
- Cell Biology
- Immunology
Background:
- Multidrug resistance (MDR) is a major challenge in cancer chemotherapy, often mediated by P-glycoprotein (P-gp) overexpression.
- Immunological approaches using immunotoxins (ITs) are being explored to overcome drug resistance.
- P-gp-expressing leukemia cell lines exhibit resistance to certain ITs, necessitating investigation into resistance mechanisms.
Purpose of the Study:
- To investigate the role of P-glycoprotein (P-gp) in mediating resistance to immunotoxins (ITs).
- To elucidate the cellular mechanisms underlying IT resistance in P-gp-expressing multidrug-resistant (MDR) cells.
- To explore potential strategies for overcoming IT resistance in cancer therapy.
Main Methods:
- Utilized P-gp-expressing (RV+ and K562) and parental (HL60) leukemia cell lines.
- Assessed cytotoxicity of immunotoxin HuM195-gelonin and other toxins (ricin A chain, cycloheximide, Pseudomonas exotoxin A).
- Investigated IT binding, internalization, intracellular trafficking (confocal microscopy), and lysosomal function (bafilomycin A).
Main Results:
- P-gp overexpression conferred resistance to the immunotoxin HuM195-gelonin and free rGelonin.
- Resistance was not due to decreased IT binding or internalization.
- MDR cells showed sensitivity to other toxins, indicating resistance was not ribosome-mediated.
- Increased lysosomal degradation of the IT in MDR RV+ cells was identified as the primary resistance mechanism.
- Resistance was partially abrogated by bafilomycin A, which inhibits lysosomal function.
Conclusions:
- P-glycoprotein (P-gp) expression contributes to immunotoxin (IT) resistance in multidrug-resistant (MDR) leukemia cells.
- Increased lysosomal degradation of ITs is a key mechanism driving this resistance.
- Targeting lysosomal pathways may offer a strategy to overcome IT resistance in cancer treatment.