1,721,234 research outputs found
Drug resistance and apoptosis in cancer treatment: development of new apoptosis-inducing agents active in drug resistant malignancies
No full textModulation of multidrug resistance (MDR) has been extensively studied in vitro and in vivo. However, several clinical trials have failed to show any important benefits in terms of response to chemotherapy or the length of survival using MDR reversing agents. This may be
due to the expression or co-expression of other drug resistance mechanisms in malignant cells. Several studies have shown that most, if not all, chemotherapeutic agents exert their anticancer
activity by inducing apoptosis; therefore, resistance to apoptosis may be a major factor limiting the effectiveness of anticancer therapy. In the last few years, effort has been made to understand the biochemical alterations of apoptotic pathways in cancer. Many of these alterations confer a multidrug resistant phenotype to malignant
cells. In this context, the new recently developed anticancer therapies based on drugs that modulate apoptosis may have importance for the treatment of tumors that are scarcely responsive to the conventional anticancer chemotherapy. In this review, we discuss the current knowledge about drug resistance, apoptosis and cancer and report the recently developed apoptosis modulating strategies that have potential therapeutic implications for the drug resistant tumors
Recognition of coherent structures in the boundary layer of a low-pressure-turbine blade for different free-stream turbulence intensity levels
No full textParticle Image Velocimetry (PIV) has been adopted to analyze the instantaneous flow field developing on a high-lift turbine blade profile operating under low and elevated free-stream turbulence conditions (FSTI). Results reported in the paper allow us to analyze the dynamics leading to transition and separation of the suction side boundary layer, looking to generation, propagation and breakdown of coherent structures observed in the two different FSTI cases. To this end, measurements have been performed in two orthogonal planes. Results obtained in the blade-to-blade plane allow the detailed characterization of the propagation of Kelvin–Helmholtz (KH) rolls generating, at low FSTI condition, as a consequence of a non-reattaching separation. Otherwise, data in the wall-parallel plane allow recognizing the presence of three-dimensional disuniformities induced at high FSTI by low and high speed streaks (Klebanoff mode). The sinuous breakdown of boundary layer streaks generates other complex three-dimensional coherent structures such as hairpin or cane-like vortices that induce transition. Proper Orthogonal Decomposition (POD) has been adopted to in depth characterize these structures, thus further explaining the mechanisms through which the free-stream turbulence intensity modify the transition/separation processes of the suction side boundary layer of an highly loaded low pressure turbine blade
Retinoids, apoptosis and cancer
No full textRetinoids are a class of natural and synthetic vitamin A analogs
structurally related to all-trans-retinoic acid (ATRA). Natural retinoids are involved in the physiology of vision and as morphogenic agents during embryonic development; they are also known to play a major role in regulating growth and differentiation of a wide variety of normal and malignant cell types, and, indeed, they can in various ways inhibit cell proliferation, induce differentiation and cell death by apoptosis. The development of new active retinoids and the identification of two distinct families of retinoid receptors has led to an increased understanding of the cellular effects of activation of these receptors and of mechanisms involved in the retinoid-induced apoptosis. In this review a brief summary of cellular pathways relevant to programmed cell death is given together with therapeutic potentialities of retinoids having apoptotic activity. Structure-activity relationship studies concerning the importance of different stereochemistry at the C9 double bond of retinoids in conferring apoptotic activity will be described. It will be also described the preparation and the potent cytotoxic and apoptotic activity of a novel class of heterocycle-bridged arotinoids
Aryl and Heterocyclic Derivatives of Combretastatin A-4 Endowed with Anticancer Properties
No full textCombretastatins are natural antimitotic agents isolated from the bark of the South African tree Combretum caffrum. Among these compounds, combretastatin A-4 (CA-4) possesses the most potent and interesting antitumor activity.
Its mechanism of action is thought to be related to tubulin-binding properties that result in rapid tumour endothelial cell damage, neovascular shutdown and subsequent haemorrhagic necrosis.
A large number of combretastatin A-4 analogues has been obtained and studied for cell-growth inhibition activity. These structural derivatives may be classified taking into account A-ring, B-ring or bridge modifications.
Following our previous experience in arotinoid field, we envisaged novel bridge modified combretastatins taking into consideration six-membered aromatic rings as bioisosteric conformationally locked double bond analogs. Terphenyl backbone is the simplest scaffold emerged from our project, and despite already known and used in other synthetic and medicinal chemistry fields, nothing was reported in the antineoplastic research. We then adopted a versatile double Suzuki coupling strategy to easily reach a series of terphenyl or diphenyl pyridine combretastatin analogs.
Besides six-membered rings, the synthesis of novel isoxazole and isoxazoline derivatives at the bridge position was envisaged to give precious information on conformationally locked combretastatins. Several possible isomers were obtained with different substitutions.
The antiproliferative activity of bridge modified combretastatins, tested on HL60 cells showed that terphenyl compounds were scarcely active, having IC50 and AC50 over 10 and 20 μM, but pyridine derivatives demonstrated much more interesting, in special way having the nitrogen placed near to ring A junction. The isoxazole and isoxazoline derivatives had also a very variable behaviour, being the 3,5 disubstituted not much active, but having the 4,5 isoxazolines the most interesting antiproliferative activity in the series of our new analogues.
It is worth noting that high potency was found for compounds bearing both cis and trans substitutions at the isoxazoline ring.
Both intrinsic (as evidenced through investigation on mitochondrial membrane potential and confirmed in experiments with a caspase-9 inhibitor) and extrinsic (interaction with Fas receptor and reduced activity towards Fas-ligand resistant cell lines) proapoptotic pathways appeared to be influenced, finally resulting in a block into G2 cell-cycle phase.
We studied different derivatives bearing the terphenyl structure, varying the substitution pattern of rings substitution. A peculiar behaviour was observed for compounds bearing a 4-carboxy group at ring B. Indeed, when tested in HL60 culture for antiproliferative activity, we observed an unexpected increase of cell population with respect to control. Following further studies, these compounds appeared to support cell viability and decrease apoptotic occurrence even in serum-free media, behaving in similar way as natural 14-hydroxy-retro-retinol (14-HRR). Moreover, these terphenyls were able to protect cultured neuronal cells treated with staurosporin (apoptotic inducer), but no protection was observed towards necrotic stimulations with glutamate. Taking into account that many neurodegenerative pathologies involve the apoptosis of neuronal populations, we think that terphenyl structures could be considered as leads for a novel protective therapeutic strategy
Stilbene derivatives as new cancer therapeutic agents
No full textStilbene derivatives exhibit killing and suppression of growth activity against a variety of cancer cells, and are effective at suppressing tumor growth in vivo. The stilbene derivatives may be used in the treatment of diseases characterized by cell hyperproliferation including human malignancies and non-malignant diseases such as liver cirrhosis. Stilbenes may also disrupt abnormal vessels in tumor to achieve vascular disrupting effect to suppress tumor growth. Water soluble pro-drug forms of stilbene derivatives are particularly useful in suppressing tumor growth in vivo
Experimental investigation of the interaction between incoming wakes and instability mechanisms in a laminar separation bubble
No full textThe present paper reports the results of a detailed experimental study on the interaction process between incoming wakes and a laminar separated boundary layer. Experimental investigations have been carried
out, for a low Reynolds number case, over a flat plate installed within a double contoured test section designed to produce an adverse pressure gradient typical of Ultra-High-Lift turbine blade profiles. Measurements
have been performed by means of a single-sensor hot-wire anemometer. The phase-locked ensemble averaging technique, synchronized with the wake frequency, has been adopted to reconstruct
the boundary layer space–time evolution in terms of ensemble-averaged velocity and velocity root mean square. These experimental data have been exploited in order to investigate how the unsteady incoming
flow interacts with the instability mechanisms of the boundary layer to drive transition. Two main effects of wake passage were found. The low frequency disturbance associated with the wake passage triggers
the Kelvin–Helmholtz instability process developing in the shear layer in the time interval between wakes. Moreover, the temporary reduction/suppression of the separation bubble observed when the
incoming wake reaches the separated flow region has been found to be driven by linear stability mechanisms, which promote a quick amplification of the high frequency velocity fluctuations carried by wakes
Numerical and Experimental Investigations of Boundary Layer Separation Control by Means of Synthetic Jets in Low Pressure Turbine Adverse Pressure Gradient Conditions
No full textA wavelet-based intermittency detection technique from PIV investigations in transitional boundary layers
No full textThe transition process of the boundary layer growing over a flat plate with pressure gradient simulating the suction side of a low-pressure turbine blade and elevated free-stream turbulence intensity level has been analyzed by means of PIV and hot-wire measurements. A detailed view of the instantaneous flow field in the wallnormal plane highlights the physics characterizing the complex process leading to the formation of large-scale coherent structures during breaking down of the ordered motion of the flow, thus generating randomized oscillations (i.e., turbulent spots). This analysis gives the basis for the
development of a new procedure aimed at determining the intermittency function describing (statistically) the transition process. To this end, a wavelet-based method has been employed for the identification of the large-scale structures created during the transition process. Successively, a probability density function of these events has been defined so that an intermittency function is deduced. This latter strictly corresponds to the intermittency function of the transitional flow computed trough a classic procedure based on hotwire data. The agreement between the two procedures in the intermittency shape and spot production rate proves the capability of the method in providing the statistical representation of the transition process. The main advantages of the procedure here proposed concern with its applicability to PIV data; it does not require a threshold level to discriminate first- and/or second-order time-derivative of hot-wire time traces (that makes the method not influenced by the operator); and it provides a clear evidence of the connection between the flow physics and the statistical representation of transition based on theory of turbulent spot propagatio
- …
