PBL (Psoralens + Blue light): how blue light activates furocoumarin derivatives triggering tumor cell apoptosis

BACKGROUND. Furocoumarins are natural and synthetic compounds with high chemotherapeutic potency under UVA irradiation. To improve their activity and avoid severe side effects likely mainly related to the formation of interstrand crosslinks (XLs) with DNA pyrimidine bases, a variety of derivatives, hopefully monofunctionals, 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. The UVA photobiological effects of furocoumarins are mainly related to their capacity to photoreact with DNA. 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 presented. RESULTS. TMA and 8-MOP show high antiproliferative activity towards cancer cells, through induction of apoptosis. Besides ROS generation (less efficient under BL than UVA), the proapoptotic effect seems related to the activation of p38 and inhibition of p44/42 phosphorylation. Interestingly, the decrease of β nuclear-catenin is coupled with dropping of CD44-positive cells. 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 are detected on isolated DNA by TMA treatment, but only MAs form. However, formation of XLs still remains for 8-MOP under BL but in a lower amount than UVA. CONCLUSIONS. Overall, our results indicate that 8-MOP, and particularly TMA, can be efficiently activated by BL and may be considered good compounds for targeted phototherapy of prostate and bladder cancers and possibly for other solid tumors.