PBL (PSORALENS + BLUE LIGHT): BLUE LIGHT ACTIVATES 8-MOP AND TMA TRIGGERING PROSTATE (DU145) AND VESICAL (T24) TUMOR CELL APOPTOSIS AND DEATH

BACKGROUND. Psoralens and angelicins (furocoumarins) are natural and synthetic compounds with high antiproliferative potency under UVA irradiation mainly used for the treatment of skin diseases (PUVA therapy) or immunological disorders in extracorporeal photopheresis (ECP). To improve their activity against psoriasis or vitiligo and avoid severe side effects mainly related to the formation of interstrand crosslinks (XLs) with DNA pyrimidine bases, a variety of derivatives, hopefully monofunctional, have been synthesized. Although angelicins, due to their angular geometry, do not generally form XLs, some of them, i.e. (TMA), can crosslink folded DNA upon UVA. Furthermore, furocoumarins produce ROS that impair cellular functions through lipid peroxidation, oxidation of guanine and strand breaks in nucleic acids, oxidation of proteins and inactivation of enzymes. To photoactivate 8- MOP and 4,6,4'-trimetylangelicin (TMA) towards human prostate (DU145 PCa) and bladder (T24) cancer cell lines, a new approach based on less toxic and more penetrating visible radiation (BL, 420 nm) is proposed. RESULTS. TMA and 8-MOP showed high antiproliferative activity towards both cancer cell lines, through induction of apoptosis. Besides ROS generation (less efficient under BL than UVA), the proapoptotic effect seemed related to the activation of p38 and inhibition of p44/42 phosphorylation. Moreover, no phosphorylation of the histone H2AX, nuclear β -catenin and GSK3β occurred. Moreover, Cyclin D1, c-Myc and CD44v6 expression were reduced through inhibition of the Wnt pathway. Overall, DU145 cells appeared more sensitive to PBL than T24, showing a specificity of the test compounds towards different tumor cell lines. The strong photocytotoxicity of TMA and 8-MOP can be related to the kind and number of DNA lesions. Under BL, no mutagenic crosslinks, no photocleavage nor photooxidative lesions were detected on isolated DNA by TMA phototreatment, but only MAs can form. However, generation of XLs still remained for 8-MOP under BL but in a lower amount than under UVA. CONCLUSIONS. Overall, our results indicate that 8-MOP, and particularly TMA, can be efficiently activated by BL and may be considered good candidates for targeted PBL of prostate and bladder cancers and possibly for other solid tumors.