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Differences in sensitivity to UVC, UVB and UVA radiation of a multidrug-resistant cell line overexpressing
G S Trindade1, M A Capella, L S Capella
1Instituto de Biofísica Carlos Chagas Filho, Rio de Janeiro, Brazil.
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.
Insights
Multidrug resistance (MDR) in leukemia cells confers resistance to UVA radiation, independent of P-glycoprotein (Pgp) efflux pump activity. UVA exposure impairs Pgp function, suggesting alternative resistance mechanisms like higher catalase activity.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Multidrug resistance (MDR) is characterized by tumor cells acquiring resistance to multiple drugs.
- The P-glycoprotein (Pgp) efflux pump is a key mechanism in MDR, extruding toxic substances from cells.
- MDR leukemia cell lines overexpressing Pgp exhibit resistance to UVA radiation.
Purpose of the Study:
- To investigate the role of P-glycoprotein (Pgp) in UVA radiation resistance in MDR leukemia cells.
- To determine if MDR modulators affect UVA resistance.
- To explore potential mechanisms underlying UVA resistance in MDR cells.
Main Methods:
- Utilized a multidrug-resistant (MDR) leukemia cell line overexpressing Pgp.
- Administered MDR modulators (verapamil, cyclosporin A) to assess their effect on UVA resistance.
- Employed flow cytometry and fluorescence microscopy to measure rhodamine 123 extrusion by Pgp.
- Assessed cell viability and catalase activity.
Main Results:
- MDR modulators did not alter resistance to UVA radiation.
- UVA treatment impaired Pgp function without significantly affecting cell viability.
- The MDR cell line exhibited higher catalase activity compared to the parental cell line.
- Results suggest Pgp is not the primary mediator of UVA resistance, and oxidative damage may affect Pgp function.
Conclusions:
- P-glycoprotein (Pgp) is not the primary determinant of UVA resistance in this MDR leukemia cell line.
- UVA radiation may directly damage Pgp, impairing its function.
- Elevated catalase activity likely contributes to UVA resistance in MDR cells.
- Further research is needed to elucidate the exact mechanisms of UVA resistance in MDR cancer cells.