BACKGROUND:The death ligand,tumor necrosis factor(TNF)related apoptosis-inducing ligand(TRAIL),induces apoptosis and non-apoptotic signaling in some tumor cells.The purpose of this study was to investigate the roles of the pro-apoptotic TRAIL receptors,TRAIL-R1 and TRAIL-R2,as well as Bcl-xL and TRAF2 in TRAIL-induced expression of the pro-inflammatory cytokine IL-8 and the invasion-promoting protein urokinase(uPA) in pancreatic ductal adenocarcinoma(PDAC) cells.METHODS:Colo357wt,Colo357/TRAF2,Colo357/Bcl-xL,Panc89 and PancTuI cells were stimulated with TRAIL and uPA and IL-8 expression was detected using real-time PCR.Antagonistic,receptor-specific antibodies were used to investigate the effects of TRAIL-R1 or TRAIL-R2 inhibition.RESULTS:Dose-dependent increases in uPA and IL-8 expression were detected following TRAIL stimulation in PDAC cells.These effects were inhibited when TRAIL-R1 but not TRAIL-R2 was blocked.Overexpression of TRAF2 or Bcl-xL strongly increased TRAIL-mediated upregulation of uPA and IL-8.CONCLUSIONS:In PDAC cells,TRAIL strongly induced uPA and IL-8 via TRAIL-R1.This response was further enhanced in cells overexpressing TRAF2 and Bcl-xL.Therefore,inhibition of the non-apoptotic 'side-effects' of TRAIL treatments by inactivation of TRAF2 and Bcl-xL might represent additional relevant strategies for the treatment of pancreatic cancer.
ABSTRACT
Malaria and leishmaniasis are potentially lethal protozoan diseases affecting a huge number of people worldwide, especially in underdeveloped countries. The alarming spread of drug resistance concerning both Plasmodium and Leishmania parasites makes the search of novel antimalarial and antileishmanial agents an urgent need. Unfortunately, at the moment even the combination therapies are failing in many regions afflicted by the diseases and alternatives are scarcely found. In addition, the available antileishmanial drugs are quite toxic, expensive and very often need monitoring and hospitalization. In the light of this dramatic situation, the discovery of novel effective, safe and affordable molecules is vital.
Thus far, several strategies have been developed to overcome resistance mechanisms; among them, of particular interest are the structural optimization of already known antiprotozoal molecules, the development of hybrid compounds and the search of new chemical scaffolds. Based on these considerations, the aim of the present thesis was the synthesis of different novel sets of molecules, potentially candidates for the treatment of malaria and/or leishmaniasis. On one hand I prepared derivatives of the antiprotozoal agents chloroquine and clofazimine, in order to improve the biological activity and to reduce resistance mechanisms. On the other hand, I explored the potenzialities of new chemical scaffolds, such as indeno[2,1-c]quinolines, to design new antimalarials. Moreover, I evaluated the possibility of creating hybrid molecules, combining moieties with different mechanism of action which could carry out a synergistic effect. In particular, the quinoline nucleus has been combined with different HDACs inhibiting structures to generate antiplasmodial hybrids, whereas aphidicolin (a fungal metabolite with antileishmanial activity) has been condensed with other molecules endowed with antileishmanial activity, such as ethyl 3-chloroacetamidobenzoate and eflornithine.
Biological assays were in general quite encouraging and suggested that these new classes of compounds could be considered as potential leads for the synthesis of new effective antiprotozoal drugs that, in some cases, could hopefully overcome resistance mechanisms.
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