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[Multidrug resistance and its reversal. General review of fundamental aspects]
1Institut Bergonié, université de Bordeaux, France.
Abstract:
Among the mechanisms by which cancer cells evade chemotherapy, multidrug resistance (MDR) is certainly the best known. MDR is characterised by cross-resistance between numerous natural products used in cancer treatment, especially antibiotics and plant alkaloids. MDR results from a defect in cell accumulation of the drugs, which are actively effluxed from cells by a plasma membrane pump, which is a high molecular weight glycoprotein termed P-glycoprotein. This protein is encoded by a gene called mdr1, and can be inhibited by a variety of pharmacological compounds. The activation of the mdr1 gene can occur via numerous types of stimulation, especially anticancer drugs themselves, which can induce mdr1 gene transcription. P-glycoprotein is an ATPase transporter which is believed to extrude xenobiotics from the plasma membrane rather than from cytoplasm. Although potential sites of interaction of P-glycoprotein with its various ligands have been identified, especially at the level of putative transmembrane domains, the exact mechanism for drug pumping has never been elucidated. Reversal of MDR in vitro is easy to obtain and to characterise. An important development aims at identifying substances able to reverse MDR in the clinical setting, that are devoid of any pharmacological properties other than interaction with P-glycoprotein. Other targets can be postulated for these MDR modulators, whose combination could well lead to a synergistic reversal of drug resistance.
Insights
Multidrug resistance (MDR) in cancer occurs when cells pump out chemotherapy drugs using P-glycoprotein. Researchers are identifying compounds to block this pump and reverse drug resistance in patients.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Multidrug resistance (MDR) is a key mechanism enabling cancer cells to evade chemotherapy.
- MDR involves cross-resistance to various natural products like antibiotics and plant alkaloids.
- This resistance stems from the efflux of drugs by P-glycoprotein, a plasma membrane pump encoded by the mdr1 gene.
Purpose of the Study:
- To explore the mechanisms of MDR in cancer cells.
- To investigate P-glycoprotein's role in drug efflux and its regulation.
- To identify agents capable of reversing MDR in a clinical setting.
Main Methods:
- Characterization of P-glycoprotein as an ATPase transporter involved in xenobiotic extrusion.
- Identification of potential interaction sites between P-glycoprotein and its ligands.
- In vitro studies on the reversal of MDR.
Main Results:
- P-glycoprotein actively effluxes drugs, preventing cellular accumulation and leading to MDR.
- The mdr1 gene transcription can be induced by anticancer drugs.
- Reversal of MDR in vitro is achievable, with ongoing efforts to find clinical MDR modulators.
Conclusions:
- P-glycoprotein is a critical target for overcoming MDR in cancer treatment.
- Developing MDR modulators that specifically interact with P-glycoprotein is a promising therapeutic strategy.
- Combination therapies targeting MDR modulators may lead to synergistic reversal of drug resistance.