Reversal of multidrug resistance of tumor cells
D Szabó1, H Keyzer, H E Kaiser
1Department of Medical Microbiology, University of Szeged, Szeged, Hungary.
Abstract:
Drug resistance to chemotherapy is rapidly emerging. Resistance to one drug carries over resistance to unrelated anticancer drugs leading to multidrug resistance (MDR). A major factor of MDR is P-glycoprotein (P-gp) mediated ABC transport found in many eukaryotic cells. P-gp acts as a drug eMux pump. The mdr1 gene involved in P-gp 170 protein production is localized in the human chromosome 7 band p2 1.0-21.1. Point mutations after cross-resistance patterns. A variety of stimuli increase the expression of the mdr1 gene: lowered extracellular pH, heat shock, arsenite, cytotoxic agents, anticancer drugs, transfection with oncogenes, HIV-I, and UV-irradiation. An alternative hypothesis to the efflux pump claims that P-gp modifies the intracellular environment to reduce accumulation of anticancer drugs in cancer cells by creating ionic or proton gradients. Chemosensitizers that block P-gp drug extrusion are generally lipid-soluble at physiological pH, possess a basic nitrogen atom and at least two co-planar rings. P-gp blocking does not depend on drug chirality. This opens the way of treating P-gp related MDR with chiral versions of drugs relatively harmless in terms of side-effects. We believe that resistance modifiers combined with cytostatics will chemotherapeutically be more effective for cancer patients.
Insights
Multidrug resistance (MDR) in cancer therapy is often mediated by P-glycoprotein (P-gp) efflux pumps. Targeting P-gp with resistance modifiers may enhance chemotherapy effectiveness and reduce side effects.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Drug resistance to chemotherapy is a significant clinical challenge, leading to multidrug resistance (MDR).
- P-glycoprotein (P-gp), a product of the mdr1 gene, is a major factor in MDR, functioning as an efflux pump that removes anticancer drugs from cells.
- Various stimuli, including cytotoxic agents and UV irradiation, can increase mdr1 gene expression.
Purpose of the Study:
- To explore the mechanisms of P-gp mediated multidrug resistance.
- To investigate the characteristics of chemosensitizers that block P-gp.
- To propose strategies for overcoming P-gp related MDR in cancer treatment.
Main Methods:
- Review of P-gp function as an efflux pump and its role in MDR.
- Analysis of factors influencing mdr1 gene expression.
- Examination of chemosensitizer properties and their interaction with P-gp.
- Consideration of alternative hypotheses for P-gp's role in drug resistance.
Main Results:
- P-gp acts as a drug efflux pump, contributing significantly to MDR.
- The mdr1 gene is located on human chromosome 7.
- Chemosensitizers that block P-gp are typically lipid-soluble, possess a basic nitrogen atom, and have at least two co-planar rings.
- P-gp blocking is independent of drug chirality.
Conclusions:
- P-gp mediated drug efflux is a critical mechanism in MDR.
- Understanding P-gp function and chemosensitizer properties can guide the development of novel cancer therapies.
- Combining resistance modifiers with cytostatics offers a promising approach to improve chemotherapeutic outcomes for cancer patients.
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