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[Calcium antagonists as modulators of multi-drug resistant tumor cells]
G Hamilton1, G Theyer, G Baumgartner
1Klinische Abteilung für Pathophysiologie, Universitätsklinik für Chirurgie, Wien.
Abstract:
Multidrug-resistance (MDR) is a cellular mechanism, which in certain tumors reduces the chemosensitivity of cells to a characteristic group of structural different cytostatic drugs, as anthracyclines, Vinca alkaloids and others, and correlates with a unfavourable clinical prognosis. In MDR-cells the intracellular concentration of cytostatic drugs is reduced due to the action of the mdr-1-gene-encoded P-glycoprotein (P-gp/gp 170), which functions as drug efflux pump with broad substrate specificity. Many calcium channel blockers of all subclasses (phenylalkylamine, dihydropyridine and benzothiazepine type) and other calcium antagonists inhibit the P-gp-mediated drug efflux and represent modulators of MDR (resistance modifiers, chemosensitizers). Since the sensitized tumor cells express no voltage-gated calcium channels, the induction of changes in intracellular free calcium showed no effect on MDR and the MDR-activity of antagonists is not correlated with their cardiovascular effects, the chemosensitization by these drugs is independent from their action on calcium channels and Ca(++)-regulation. Photoaffinity labelling with reactive derivatives proved the direct competitive interaction of calcium antagonists with the binding site of P-gp for cytostatic drugs as mechanism of action. The MDR-modulation of the doxorubicin or Vinca alkaloid resistance of tumor cells in vitro by verapamil and other calcium channel blockers was confirmed in vivo as increased survival length in mice with tumor transplants in combination with cytostatic therapy. The clinical application of calcium antagonists is limited by their severe cardiovascular side effects associated with the high concentrations required for successful reversal of MDR.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Calcium channel blockers can reverse multidrug resistance (MDR) in tumors by inhibiting P-glycoprotein drug efflux. This chemosensitization is independent of calcium channel activity, offering potential for improved cancer therapy.
Area of Science:
- Pharmacology
- Cancer Biology
- Molecular Medicine
Background:
- Multidrug resistance (MDR) in tumors reduces chemotherapy effectiveness against cytostatic drugs.
- P-glycoprotein (P-gp/gp 170), encoded by the mdr-1 gene, acts as a drug efflux pump in MDR cells, lowering intracellular drug concentrations.
- MDR correlates with poor clinical prognosis.
Purpose of the Study:
- To investigate the role of calcium channel blockers as modulators of MDR.
- To elucidate the mechanism by which calcium channel blockers affect P-gp-mediated drug efflux.
- To assess the in vitro and in vivo efficacy of calcium channel blockers in reversing MDR.
Main Methods:
- Photoaffinity labeling to study drug-target interactions.
- In vitro experiments using tumor cells to assess drug resistance reversal.
- In vivo studies using tumor-bearing mice to evaluate survival rates.
Main Results:
- Calcium channel blockers, including verapamil, inhibit P-gp-mediated drug efflux, acting as MDR modulators or chemosensitizers.
- Chemosensitization by these drugs is independent of their effects on calcium channels or intracellular calcium regulation.
- Direct competitive interaction between calcium antagonists and P-gp for cytostatic drugs was demonstrated.
- In vivo studies showed increased survival in mice treated with cytostatics and calcium channel blockers.
Conclusions:
- Calcium channel blockers can directly interact with P-glycoprotein, reversing MDR in tumor cells.
- This MDR modulation offers a potential strategy to enhance chemotherapy efficacy.
- Clinical application is limited by cardiovascular side effects at high required concentrations.