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Cancer is the leading cause of death due to non-communicable diseases worldwide. Despite the advances in the development of new antitumor drugs, there are still problems such as the resistance that tumor cells acquire against them, as well as the serious side effects observed after their application. In this thesis, three new families of compounds have been studied as possible antitumor drugs. The first one, a ribonuclease called NLSPE5 that has been modified by protein engineering, and the other two are metallic compounds based on manganese (Mn) and iron (Fe). The results obtained indicate that NLSPE5, in addition to altering the epigenetic pattern of the tumor cell lines, decrease their capacity to migrate and invade nearby tissues. On the other hand, the results of the investigation of the new Mn-based compounds show that, of all of them, Mn8 has a strong antitumor effect on lung and ovarian tumor cell lines. This effect is similar to that observed with commercial antitumor drugs such as Cis-platinum. The results also indicate that Mn8 breaks the DNA of the cancer cells in presence of reactive oxygen species. It was also observed that this compound causes cell death by apoptosis. Finally, the results of the study of Fe-based compounds show that all of them are highly cytotoxic against lung and ovarian tumor lines, and as well as Mn8, these compounds break DNA in presence of reactive oxygen species. Among the different Fe-based compounds, compound 10 showed the highest selectivity for tumor lines. Moreover, this compound induces apoptosis and reduces the migration capacity of a cancer cells. In conclusion, all the investigated compounds are very promising as antitumor drugs El càncer és la principal causa de mort per malalties no transmissibles a nivell mundial. Malgrat els avenços en el desenvolupament de nous fàrmacs contra el càncer, continuen presentant-se problemes com la seva resistència a aquests, així com els greus efectes secundaris observats després de la seva aplicació. A causa d'això, en aquesta tesi s'han estudiat tres noves famílies de compostos com a possibles fàrmacs antitumorals. En el primer cas, una ribonucleasa anomenada NLSPE5 que ha estat modificada mitjançant enginyeria de proteïnes i, d’altra banda, compostos metàl·lics basats en manganès (Mn) i ferro (Fe). Els resultats obtinguts indiquen que NLSPE5 a més d'alterar el patró epigenètic de les línies tumorals, interfereix en la capacitat que tenen aquestes per a migrar i envair teixits pròxims. D'altra banda, els resultats de la recerca dels nous compostos basats en Mn mostren que, de tots ells, el Mn8 té un gran efecte antitumoral sobre línies tumorals de pulmó i d'ovari, i que aquest efecte és similar al que s'observa amb antitumorals comercials com el Cis-platí. Els resultats indiquen a més que el Mn8 trenca el DNA de les cèl·lules tumorals en presència d’espècies reactives d’oxigen. Es va observar també que aquest compost provoca mort cel·lular per apoptosi. Finalment, els resultats de l'estudi dels compostos basats en Fe mostren que tots ells són molt citotòxics enfront de les línies tumorals de pulmó i ovari, i, igual que el Mn8, trenquen el DNA en presència d’espècies reactives d’oxigen. De tot el grup de compostos basats en Fe, el compost 10 va mostrar la major selectivitat per les cèl·lules tumorals. A més es va veure que aquest compost provoca apoptosi i redueix la capacitat de migració de cèl·lules de càncer. En conclusió i sobre la base dels resultats obtinguts podem esmentar que tots els compostos investigats són molt prometedors com a agents antitumorals Programa de Doctorat en Biologia Molecular, Biomedicina i Salut

Purpose of review The diagnosis of drug-induced interstitial lung disease (DI-ILD) is challenging and mainly made by exclusion of other possible causes. Toxicity can occur as a cause of drug(s) or drug-drug interactions. In this review, we summarize the possible role of pharmacogenetics of metabolizing enzymes in DI-ILD. Recent findings Knowledge of the genetic predispositions of enzymes involved in drug metabolization and their relation with proposed cytotoxic mechanisms of DI-ILD, in particular direct cell toxicity and free oxygen radical production is increasing. The cytochrome P450 enzyme family and other enzymes play an important role in the metabolism of all sorts of ingested, injected, or inhaled xenobiotic substances. The liver is the major site for metabolism. Metabolic cytotoxic mechanisms have however also been detected in lung tissue. Polymorphisms in genes coding for enzymes that influence metabolic activity may lead to localized (toxic) reactions and tissue damage. This knowledge may be helpful in preventing the risk of DI-ILD. Drug toxicity can be the consequence of absence or very poor enzyme activity, especially if no other metabolic route is available. In the case of reduced enzyme activity, it is recommended to reduce the dose or to prescribe an alternative drug, which is metabolized by a different, unaffected enzyme system to prevent toxic side effects. However, enhanced enzyme activity may lead to excessive formation of toxic and sometimes reactive metabolites. Therefore, knowing a patient's drug-metabolizing profile before drug prescription is a promising way to prevent or explain DI-ILD.

Scientific report

Scientific report.

Light at wavelength 405 nm is an effective bactericide. Previous studies showed that exposing mammalian cells to 405 nm light at 36 J/cm(2) (a bactericidal dose) had no significant effect on normal cell function, although at higher doses (54 J/cm(2)), mammalian cell death became evident. This research demonstrates that mammalian and bacterial cell toxicity induced by 405 nm light exposure is accompanied by reactive oxygen species production, as detected by generation of fluorescence from 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate. As indicators of the resulting oxidative stress in mammalian cells, a decrease in intracellular reduced glutathione content and a corresponding increase in the efflux of oxidised glutathione were observed from 405 nm light treated cells. The mammalian cells were significantly protected from dying at 54 J/cm(2) in the presence of catalase, which detoxifies H2O2. Bacterial cells were significantly protected by sodium pyruvate (H2O2 scavenger) and by a combination of free radical scavengers (sodium pyruvate, dimethyl thiourea (OH scavenger) and catalase) at 162 and 324 J/cm(2). Results therefore suggested that the cytotoxic mechanism of 405 nm light in mammalian cells and bacteria could be oxidative stress involving predominantly H2O2 generation, with other ROS contributing to the damage.

Saponins are natural glycosides which possess a wide range of pharmacological properties including cytotoxic activity. In this review, the recent studies (2005–2009) concerning the cytotoxic activity of saponins have been summarized. The correlations between the structure and the cytotoxicity of both steroid and triterpenoid saponins have been described as well as the most common mechanisms of action.

Insulin-dependent diabetes mellitus (IDDM) results from a chronic autoimmune destruction of the pancreatic  -cells. Despite well-recognized role of the cellular immune system, it has become apparent that multiple effector molecules participate in the complex sequence of  -cell destruction. Recent evidence suggests that oxidative damage, resulting from both cytokine-induced production of toxic free radicals and low antioxidant capacity of the  -cell plays a significant role in the pathogenesis of IDDM. However, the production of common toxic free radicals (e.g. nitric oxide and/or reactive oxygen species), including its potentially different origin, is still an uncertain model for the specific  -cell injury. Possible role of antioxidant molecules in the etiology of diabetes received little attention so far, despite the pronounced diabetogenic action of the oxidative derivatives of ascorbic, and, particularly, uric acid. Our research evaluated the oxidant vs. antioxidant balance in the progression of diabetes mellitus. Results indicate that prediabetic condition, apart from well-established immunological and metabolic alterations, could be associated with biochemical changes revealing complex disturbances of the antioxidant defense system. Possible implications of these phenomena would at best be elucidated by studying the physiologically relevant mechanisms of the production of highly selective  -cytotoxins from the antioxidant compounds, and their influence on the  -cell function. The research on this topic is currently in progress in our laboratory.