Evaluation of the activity of photoactivatable compounds under different irradiation conditions on human cancer cell lines for photochemotherapeutic applications

ABSTRACT During these 3 years of PhD course, my research activity has focused on the evaluation of the antiproliferative activity of known photosensitizing compounds, using activation under different selected wavelengths. Evaluation of 8-Methoxypsoralen (8-MOP) and 4,6,6’-Trimethylangelicin (TMA) antiproliferative activity in combination with Blue Light irradiation Psoralens and angelicins are known photosensitizing agents, used in combination with UVA light (PUVA) for the treatment of a variety of diseases (i.e. psoriasis, vitiligo, mycosis fungoides, Graft-versus-Host disease, cutaneous T-cell lymphoma). Although this therapeutic approach proved to be highly effective, side effects may occur with PUVA therapy, including skin cancer (squamous cell carcinoma and basal cell carcinoma). The use of UVA irradiation also limits the light penetration into tissues, restricting the application of this therapeutic approach to superficial areas and it is known to cause DNA damages. Previous studies indicated that psoralens can be activated with longer wavelengths (417 nm), with a reduced formation of mutagenic lesions, such as DNA crosslinks. These evidences gave us the idea to use blue light (BL) for the activation of psoralens, in order to reduce the toxicity of the treatment and to extend the application of this therapeutic approach to solid tumors as BL is also more penetrating than UVA. Thus, the antiproliferative activity of 8-MOP and TMA was evaluated in combination with blue light on DU145 human prostate cancer cell line, along with the detection of DNA damages, ROS generation inside the cells and western blot analysis of proapoptotic, prosurvival and proliferative molecular pathways. Flow cytometry was used for the determination of cell death mechanism and to analyse the expression of CD44 receptors, which are markers for stem cell features. Potential anticancer activity of Fluphenazine activated with UVA light Fluphenazine (FPZ) is an antipsychotic agent from the phenothiazine family. It exerts its activity by blocking postsynaptic D2 dopamine receptors in the limbic, cortical system and basal ganglia areas of the brain. Blocking the action of dopamine, it reduces the hallucinations and delusions that are associated with schizophrenia. FPZ has a wide adverse effect profile, including extrapyramidal symptoms (akathisia, tremors, dyskinesia). In particular, fluphenazine induces photosensitization in patients exposed to sunlight as adverse effect. Exploiting this last side effect of FPZ under light exposure, its cytotoxic activity in combination with UVA light was investigated on three different cell line.