Abstract
To explain a paradoxical radiosensitizing effect of rosmarinic acid (RA) on the melanoma B16F10 cells, we analyzed the glutathione (GSH) intracellular production on this cell (traditionally considered radioresistant) in comparison with human prostate epithelial cells (PNT2) (considered to be radiosensitive). In PNT2 cells, the administration of RA increased the total GSH content during the first 3 h (p < 0.01) as well as increased the GSH/oxidized glutathione (GSSG) ratio in all irradiated cultures during all periods studied (1h and 3h) (p < 0.001), portraying an increase in the radioprotective capacity. However, in B16F10 cells, administration of RA had no effect on the total intracellular GSH levels, decreasing the GSH/GSSG ratio (p < 0.01); in addition, it caused a significant reduction in the GSH/GSSG ratio in irradiated cells (p < 0.001), an expression of radioinduced cell damage. In B16F10 cells, the administration of RA possibly activates the metabolic pathway of eumelanin synthesis that would consume intracellular GSH, thereby reducing its possible use as a protector against oxidative stress. The administration of this type of substance during radiotherapy could potentially protect healthy cells for which RA is a powerful radioprotector, and at the same time, cause significant damage to melanoma cells for which it could act as a radiosensitive agent.
Highlights
Rosmarinic acid (RA) is a common ester derived from caffeic acid and (R)-(+)-3-(3,4dihydroxyphenyl) lactic acid present in many plant species
Different studies suggest that an increase in GSH levels is involved in cellular resistance to radiotherapy and chemotherapy, while the depletion of endogenous GSH levels is thought to increase the efficacy of treatments with ionizing radiation or depletion of endogenous GSH levels is thought to increase the efficacy of treatments with ionizing Arandtioixaitdiaonnts o20r2c0h, 9e,m12o91therapeutic agents [14,15,16,17,18,19]
In the control cultures (C) statistically significant differences in the concentrations of total GSH were determined between the two cell lines studied (p < 0.001); during the two post-irradiation periods studied (1h and 3h) a greater amount of total GSH was determined in the B16F10 melanoma cells which was double the total GSH concentration determined in the PNT2 cells (Figure 3a)
Summary
Rosmarinic acid (RA) is a common ester derived from caffeic acid and (R)-(+)-3-(3,4dihydroxyphenyl) lactic acid present in many plant species. RA has been shown to have significant antigenotoxic and radioprotective capacities in different normal and tumor cell lines against damage induced by ionizing radiation (X-rays and gamma radiation) and by ultraviolet radiation [4,5,6,7,8,9,10]. It has been shown to paradoxically increase radioinduced cellular damage in B16F10 metastatic melanoma cells, and acts as a radiosensitizing agent [11]. Cellular radioresistance in numerous healthy and tumor cell lines is mediated by increased glutathione (GSH) synthesis that leads to the elimination of ROS produced both by exposure to ionizing radiation and chemotherapy [12,13]. Numerous authors suggest that the inc2reoaf s1e3 or reduction in intracellular GSH levels caused either by activating or blocking its synthetic cmheecmhoatnhiesmraspeauftfieccat gbeontths [1n4o–r1m9a].l Haonwdetvuemr, onrumceelrlos,usmaauktihnogrstshuegsgeessteltehcattivtheetirnecartemaseentormreodduaclittiioens iinneinfftercatcievleluinlarcaGnScHerlpevateilesnctasu[s2e0d].either by activating or blocking its synthetic mechanisms affect both normIanl athnids tsutumdoyr, cwelelsa, nmaalykzinegd tthheeserasdeiloecptriovteetcrteivatemeeffnetcmt oofdRalAitioesnininetffraeccteilvluelianr cGanSHcerlepvaetlisenintsc[e2l0l]s. tradiItniotnhailslystcuodnys,idweereadnaralydzioedsetnhseitirvaedi(ohpurmotaenctpivreosetffateectepofitRheAliaolncienlltsr)acaenldlutlhaer GefSfeHctlepvroeldsuicnedcebllys tRrAadoitniotnhaelalyvaciolanbsiilditeyreodf GraSdHioisneontshiteirvece(lhlsucmonansidperoresdtartaedeipoistehnesliitailvcee(lBls1)6aFn1d0 mtheelaenffoemctapcreoldlsu)cwedhibcyh RcoAulodnjtuhsetiafyvathiliasbpilaitryadoof xGiScaHl rinadoitohseerncseitlilzsicnognesfidfeecrte.dPoratedniotisaelnlys,ittihvee s(iBm16uFlt1a0nmeoeulasnaodmmainciesltlrsa) twiohnicohf cthoiusldtyjpuestioffy stuhbisstpaanrcaedsoaxliocnagl rwaditiohserandsiitaitziionng aetfftehcet. sPaomteenttiimalely,cothueldsipmruoltteacnt ehoeuasltahdymcienlliss,trwathioilne oafllothwisintgypesigonf isfuicbasnttandceasmaalgoengtwo itmh erlaadnioamtioan acetltlhs;e sthamesee tifminedicnogusldspurgogteecstt htehaelthpyocsesilblsi,liwtyhiolef ainllcoowrpinograstiignngifithcaisnht idthaemrtaogeimtopomsesliabnleotmoapceerfllosr;mthterseeafitmndeinntgsstrsautgeggyesttotpheatpieonstssibuinlidtyerogfoinincgorrpaodriaattiinogn tthhiesrahpityh.erto impossible to perform treatment strategy to patients undergoing radiation therapy
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