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A pleiotropic defect reducing drug accumulation in cisplatin-resistant cells
Xing-Jie Liang1, Ding-Wu Shen, Michael M Gottesman
1Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Room 2108, Bethesda, MD 20892-4254, USA.
Journal of Inorganic Biochemistry
|October 2, 2004
Summary
Tumor resistance to cisplatin, a common cause of cancer treatment failure, stems from reduced drug accumulation. This occurs due to defective cell surface protein expression and impaired endocytosis in cisplatin-resistant (CP-r) cells.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Cisplatin resistance in tumors is a significant obstacle to effective cancer treatment.
- Cisplatin-resistant (CP-r) cancer cells exhibit multiple, simultaneous genetic and cellular alterations.
- Understanding the mechanisms underlying CP-r is crucial for developing strategies to overcome treatment failure.
Purpose of the Study:
- To investigate the cellular alterations responsible for cisplatin resistance.
- To determine if single-step selection can identify key mechanisms of resistance.
- To elucidate the role of drug accumulation and transport in CP-r.
Main Methods:
- Isolation of single-step cisplatin-resistant (CP-r) variants.
- Pulse-chase labeling and biotinylation of cell surface proteins.
- Analysis of membrane protein recycling, lysosomal acidification, and endocytosis.
Main Results:
- Reduced drug accumulation is a hallmark of CP-r cells, often due to dominant gene action.
- CP-r cells display mislocalized membrane proteins, linked to defective plasma membrane recycling and lysosomal acidification.
- Decreased expression of folate-binding protein, arsenic-binding proteins, and impaired endocytosis contribute to reduced uptake of platinum-based drugs and related compounds.
Conclusions:
- Cisplatin resistance involves multiple mechanisms that limit intracellular drug accumulation.
- Defective cell surface protein expression (transporters, carriers) and reduced endocytosis are key contributors to CP-r.
- Targeting these mechanisms may enhance the efficacy of platinum-based chemotherapy.