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Resistance mechanisms associated with altered intracellular distribution of anticancer agents
A K Larsen1, A E Escargueil, A Skladanowski
1Laboratory of Biology and Pharmacology of DNA Topoisomerases, CNRS UMR 8532, Institut Gustave-Roussy, PR2, Villejuif, France. aklarsen@igr.fr
Abstract:
The resistance of tumor cells to anticancer agents remains a major cause of treatment failure in cancer patients. The term multidrug resistance (MDR) is used to define a resistance phenotype where cells are resistant to multiple drugs with no obvious structural resemblance and with different molecular targets. It is now clear that MDR is always multifactorial. The intracellular drug distribution is modified in many MDR cell lines, leading to increased drug sequestration in acidic vesicles, such as the trans-Golgi apparatus, recycling endosomes, and lysosomes, followed by transport to the plasma membrane and extrusion into the external medium. Since most anticancer agents target DNA or nuclear enzymes, sequestration of drug in cytoplasmic organelles will lead to decreased drug-target interaction and thereby, decreased cytotoxicity. Altered intracellular drug distribution is usually associated with the expression of drug efflux pumps, such as the P-glycoprotein and the multidrug resistance protein. Another common modification in MDR cells is alkalization of the intracellular pH. The relationship between these different resistance mechanisms is reviewed and a model proposed that suggests why these different resistance mechanisms are co-expressed in multiple cell lines.
Insights
Multidrug resistance (MDR) in tumor cells stems from altered drug distribution and pH changes, leading to treatment failure. Understanding these mechanisms is key to overcoming cancer drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Tumor cell resistance to anticancer agents is a primary reason for treatment failure.
- Multidrug resistance (MDR) involves resistance to structurally diverse drugs with different molecular targets.
- MDR is a complex, multifactorial phenomenon.
Purpose of the Study:
- To review the relationship between different MDR mechanisms.
- To propose a model explaining the co-expression of these resistance mechanisms.
Main Methods:
- Review of existing literature on MDR mechanisms.
- Analysis of altered intracellular drug distribution.
- Examination of drug efflux pump expression (e.g., P-glycoprotein).
- Investigation of intracellular pH modifications.
Main Results:
- MDR involves altered intracellular drug distribution, with drugs sequestered in acidic vesicles and extruded from cells.
- This sequestration reduces drug-target interactions and cytotoxicity.
- Alkalization of intracellular pH is a common feature in MDR cells.
- Expression of drug efflux pumps like P-glycoprotein is frequently observed.
Conclusions:
- Altered intracellular drug distribution and pH changes are key components of MDR.
- These mechanisms are often co-expressed, contributing to treatment failure.
- A proposed model explains the coordinated expression of these resistance factors.