engleski

Inhibition of multidrug resistance in murine lymphoma cells by novel dihydropyridine derivative

Multidrug resistance, the principal mechanism by which cancer cells develop resistance to chemotherapy drugs, is a major factor in the failure of many forms of chemotherapy. There may be several mechanisms involved in the development of multidrug resistance and the best characterized one involves a membrane localized P-glycoprotein. This protein accomplishes drug resistance through its action as a drug efflux-pump by reducing the intracellular concentration of anticancer drugs. Expression of MDR1 (multidrug resistance protein 1) that belongs to P-glycoprotein family is up regulated during stressful stimuli such as chemotherapy. The enhancement of MDR1 by reactive oxygen species in tumour cells is of particular interest because many anticancer treatments (e.g. radiotherapy and doxorubicin chemotherapy) relay on cytotoxicity of reactive oxygen species. Thereby, multidrug resistance inhibitors with antioxidant potential would be useful in treating cancer patients whose tumours are resistant to multiple chemotherapies. Such chemicals might prevent reactive oxygen species increase in tumour cells and concomitant increase in P-glycoprotein that leads in multidrug resistance, thus, facilitate cancer treatment. The effects of novel amphiphilic dihydropyridine derivative, denoted as K-2-11, with antioxidant properties were tested on L5178Y mouse mdr1-expressing T-cell lymphoma cells (MDR - transfected with PHA mdr1/A retrovirus) and in their parental control L5178Y cell line (PAR). Multidrug resistance reversal property of K-2-11 was verified by flow cytometry. The effects of K-2-11 used alone or in combination with doxorubicin were studied by determination of cell viability by MTT assay ; cell proliferation by 3H-thymidine incorporation assay and production of reactive oxygen species by fluorescence. K-2-11 caused complete reversal of multidrug resistance of the MDR cells being much more efficient than verapamil. Accordingly, the cytotoxic effects of doxorubicin were enhanced by K-2-11 both in MDR and in PAR cells, while K-2-11 alone did not affect cell viability. K-2-11 acted also as antioxidant reducing the cellular generation of reactive oxygen species. These results indicate a great potential of K-2-11 as novel antioxidant with very potent multidrug resistance blocking ability that should be studied further in adjuvant anticancer treatments.

multidrug resistance; dihydropyridine derivative

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