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• W2314055871 abstract "Study of mechanism of action of the phototoxicity of drugs and of new natural compounds endowed with antiproliferative activity.In recent years it has been observed an increase of clinical cases on the phototoxicity of drugs, this fact is probably due to changes in lifestyle and to a greater number of drugs present on the market. In this study we have examined the mechanisms of phototoxicity of Fluvastatin and the Pitavastatin two HMG-CoA reductase inhibitors.Initially it was observed that these drugs when in aqueous solution, can form different photoproducts, after the irradiation with UVA . The photoproducts were separated by HPLC and characterized by mass spectrometry and NMR. For the fluvastatin it was isolated a photoproduct in sufficent quantity ( FP6), while for pitavastatin were isolated two photoproduct (PP3 and PP4). The phototoxicity of these drugs and that of their photoproduct were tested on the human keratinocytes cell line NCTC 2544. The cell phototoxicity was evaluated by the MTT test after 72h from the irradiation, in presence of the two drugs and submitted at different doses of UVA and different concentrations. The photoproducts were also evaluate for they potential phototoxicity. The results obtained show a reduction in the cell viability dependent of the dose of UVA administered and of the concentration of drug used, and interestingly it was noted that the photoproducts are much more phototoxic than the parent compound. After through the use of the flow cytometry it was demonstrate that these drugs and their photoproduct are able to induce necrosis as a major made of cell death as a result of the incorporation of the propidium in the irradiated cell in the presence of the compounds examined . Furthermore, this was confirmed also by a strong depletion of the cellular ATP level and by the absence of mitochondrial depolarization. Moreover further experiments have shown an increase of intracellularcalcium due to a damage induced to the cell membrane after the phototoxic insult. To confirm this hypothesis we have observed after treatment high levels of membrane lipids peroxidation. This data suggest that the phototoxic mechanism of these drugs are mediatates by the formation of photoproducts and/or reactive species (radicals, ROS) have the membrane cell as target over which they exercise their photoxic effects.Another study carried out in this thesis regards the analysis of natural compounds as anticancer agents. The substances present in nature have for centuries known for their healing proprieties and in the last years have become very important for the research and the development of new drugs, in fact many of them have a natural origin. The compounds evaluated were extracted from Ferula the ferula communis, ferulago campestris and of the ferula glauca, a plant belonging to the family ofUmbrellifere. These plants have been much studied for their antimicrobial, estrogenic, and antiviral activity and for their cytotoxic properties. Initially was evaluated the cytotoxicity of different compounds on six cell line, three lines from solid tumors and three leukemia cell lines. From this screening we have identified four compounds structurally related to daucane esters endowed with high cytotoxicity activity especially on the leukemic cell lines. The activity of the four compound was analyzed on the cell cycle and for their proapoptotic activity . Of these four compounds, all showed a block of cell cycle in the G1 phase but only two have a high proapoptotic activity, so we proceeded to further study these compounds named DE 8, and DE 11.In the leukemia T-cell line Jurkat, it was evaluated the ROS production (reactive oxygen species) and it was examined the mitochondrial potential, and it was observed after one hour of incubation, a high ROS production while the depolarization of mitochondrial potential occurred later at longer times, indicating that the ROS production is due to the molecule itself, and not as a result of the mitochondrial depolarization. To confirm that the cell death occurred for the early ROS production, the cells were incubated with well-known scavenger of ROS such as Nacetylcisteine, Tocoferol e Butylhydroxyanisol. The results obtained have showed a significant increase of the cellular survival in the cell treated with DE-8 togheter with the inhibitor of ROS, respect to the cells treated alone with the compound. The cell were incubated also with the an Pancaspase inhibitor, Z-Vad, demonstrating also in this case un increase of the cellular viability, suggesting that the apoptosis is caspase- dependent" @default.
• W2314055871 created "2016-06-24" @default.
• W2314055871 creator A5068894244 @default.
• W2314055871 date "2012-01-26" @default.
• W2314055871 modified "2023-09-27" @default.
• W2314055871 title "Study of mechanism of action of the phototoxicity of drugs and of new natural compounds endowed with antiproliferative activity" @default.
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