Differences in Sensitivity to UVC, UVB and UVA Radiation of a Multidrug‐Resistant Cell Line Overexpressing P‐Glycoprotein

Abstract

Multidrug resistance (MDR) is the phenomenon in which cultured tumor cells, selected for resistance to one chemotherapeutic agent, simultaneously acquire resistance to several apparently unrelated drugs. The MDR phenotype is multifactorial. The best-studied mechanism involves the expression of a membrane protein that acts as an energy-dependent efflux pump, known as P-glycoprotein (Pgp), capable of extruding toxic materials from the cell. In this work, resistance to UVA radiation, but not to UVC nor UVB, was observed in an MDR leukemia cell line. This cell line overexpresses Pgp. To study the role of Pgp in the resistance to UVA radiation, two MDR modulators or reversing agents (verapamil and cyclosporin A) capable of blocking Pgp activity were used. Cell viability was assessed and the techniques of flow cytometry and fluorescence microscopy were employed to measure the extrusion of rhodamine 123 by the efflux pump. The results show that MDR modulators did not modify the resistance to UVA radiation. Furthermore, although cell viability was not significantly altered, Pgp function was impaired after UVA treatment, suggesting that this glycoprotein may be a physical target for oxidative damage, and that other factors may be responsible for the UVA resistance. In agreement with this, it was found that the resistant cell line presented a higher catalase activity than the parental (non-MDR) cell line.

Multidrug resistance in tumour cells: characterisation of the multidrug resistant cell line K562-Lucena 1

“…Many authors have suggested that the acquisition of the MDR phenotype is accompanied by modifications of the cytoskeleton such as increased expression of actin and/or tubulin and alterations on the organisation of stress fibres, microtubules and the Golgi complex (Lee et al 1993, Lee 1995, Seidel et al 1995, Erokhina et al 1994. In agreement with these observations, Lucena 1 cells were shown to express higher levels of actin m-RNA and of the proteic subunits a and b-tubulin, when compared to the parental K562 (Trindade et al 1998). It is still unclear the role played by the modifications observed in the cytoskeleton on the MDR phenotype.…”

Effects of permeability transition inhibition and decrease in cytochrome c content on doxorubicin toxicity in K562 cells

“…It must be noted, however, that P-gp inhibition did not systematically restore DOX cytotoxicity in P-gp overexpressing cells (success (Smyth et al, 1998;Fukushima et al, 2000); failure (Campone et al, 2001)). Moreover, cells overexpressing P-gp have also been reported to resist to non-P-gp substrates such as cytosine arabinoside, staurosporine, UV irradiation, Fas receptor ligation and serum starvation (Smyth et al, 1998;Trindade et al, 1999;Campone et al, 2001). Taken together, these findings suggest that other mechanisms of resistance may exist in addition to P-gp overexpression.…”

A Light in Multidrug Resistance: Photodynamic Treatment of Multidrug-Resistant Tumors

“…Pgp seems to be a target for oxidative damage, a fact we also observed when irradiating MDR leukemia cells with ultraviolet A radiation or treating them with hydrogen peroxide [54]. Thus, PDT can also possibly be used as a modulator of the MDR phenotype, when applied together with chemotherapeutics.…”