Background The evasion from apoptosis is a common strategy adopted by most tumors, and inhibitors of apoptosis proteins (IAPs) are among the most studied molecular and therapeutic targets. BIRC3 (cellular IAP2) and BIRC5 (survivin) are two of the eight members of the human IAPs family. This family is characterized by the presence of the baculoviral IAP repeat (BIR) domains, involved in protein-protein interactions. In addition to the BIR domains, IAPs also contain other important domains like the C-terminal ubiquitin-conjugating (UBC) domain, the caspase recruitment (CARD) domain and the C-terminal Ring zinc-finger (RING) domain. Main body BIRC3 and BIRC5 have been characterized in some solid and hematological tumors and are therapeutic targets for the family of drugs called “Smac mimetics”. Many evidences point to the pro-survival and antiapoptotic role of BIRC3 in cancer cells, however, not all the data are consistent and the resulting picture is heterogeneous. For instance, BIRC3 genetic inactivation due to deletions or point mutations is consistently associated to shorter progression free survival and poor prognosis in chronic lymphocytic leukemia patients. BIRC3 inactivation has also been associated to chemoimmunotherapy resistance. On the contrary, the progression from low grade gliomas to high grade gliomas is accompanied by BIRC3 expression increase, which bears relevant prognostic consequences. Due to the relationship between BIRC3, MAP3K14 and the non-canonical NF-kB pathway, BIRC3 inactivation bears consequences also on the tumor cells relying on NF-kB pathway to survive. BIRC5, on the contrary, is commonly considered an anti-apoptotic molecule, promoting cell division and tumor progression and it is widely regarded as potential therapeutic target. Conclusions The present manuscript collects and reviews the most recent literature concerning the role played by BIRC3 and BIRC5 in cancer cells, providing useful information for the choice of the best therapeutic targets.

Resveratrol (RSV), a plant-derived stilbene, induces cell death in Hodgkin lymphoma (HL)-derived L-428 cells in a dose-dependent manner (IC50 5 27 lM, trypan blue exclusion assay). At a lower range (25 lM), RSV treatment for 48 hr causes arrest in the S-phase of the cell cycle, while at a higher concentration range (50 lM), apoptosis can be detected, with activation of caspase-3. The histone/protein deacetylase SIRT1 has been described as a putative target of RSV action in other model systems, even though its role in cancer cells is still controversial. Here we show that RSV, at both concentration ranges, leads to a marked increase in p53, while a decrease of SIRT1 expression level, as well as enzyme activity, only occurred at the higher concentration range. Concomitantly, however, treatments at both concentration ranges resulted in a marked increase in K373-acetylated p53 and lysine-acetylated FOXO3a. Immunohistochemical stainings of human lymph nodes show a preferential distribution of SIRT1 in the germinal center of the follicles while the mantle zone shows nearly no staining to few positive cells. The classical HL-affected lymph nodes show a strong positivity of the diagnostic Hodgkin Reed-Sternberg cells. Notably, both the HL-derived cell lines and the Hodgkin Reed-Sternberg cells of the affected lymph nodes derive from germinal center-derived B cells. The study of SIRT1 distribution and expression on a larger number of biopsies might disclose a novel role for this histone/protein deacetylase as therapeutic target.Plant polyphenols are a class of natural molecules well known for their wide range of beneficial properties. [1][2][3] Resveratrol (RSV) is a polyphenol belonging to the class of the stilbenes present in many vegetables and fruits including grapes. The manifold properties of RSV span from chemopreventive action to antioxidant activity, promotion of tissue differentiation, modulation of adipogenesis and antiproliferative effect in several tumoral experimental models. 4-15The information currently available concerning the effects of this natural chemopreventive agent on human lymphoma cells and experimental models is limited. Although there are reports on the antiproliferative activity of RSV on different leukemia and lymphoma cell lines, [16][17][18] no data are available to date in the literature concerning the effects of RSV on Hodgkin lymphoma (HL) cell lines. HL is a tumor frequently affecting adolescents and young adults and represents about 11% of all the diagnosed lymphomas in the United States. 19,20 Furthermore, no studies addressed the involvement of the histone/protein deacetylase SIRT1 (one of the key RSV targets) and of its downstream substrates in lymphomas.Therefore, the initial aims of our work have been the assessment of the potential antiproliferative activity of RSV in the HL-derived L-428 cell line. Next, we examined various apoptosis criteria and cell cycle changes following the RSV treatment. We demonstrate the dose-dependent increase of the proportion of early and late apopto...

Resveratrol (3,4',5 trihydroxy-trans-stilbene) is one of the best known phytophenols with pleiotropic properties. It is a phytoalexin produced by vine and it leads to the stimulation of natural plant defenses but also exhibits many beneficial effects in animals and humans by acting on a wide range of organs and tissues. These include the prevention of cardiovascular diseases, anti-cancer potential, neuroprotective effects, homeostasia maintenance, aging delay and a decrease in inflammation. Age-related macular degeneration (AMD) is one of the main causes of deterioration of vision in adults in developed countries This review deals with resveratrol and ophthalmology by focusing on the antioxidant, anti-inflammatory, and anti-angiogenic effects of this molecule. The literature reports that resveratrol is able to act on various cell types of the eye by increasing the level of natural antioxidant enzymatic and molecular defenses. Resveratrol anti-inflammatory effects are due to its capacity to limit the expression of pro-inflammatory factors, such as interleukins and prostaglandins, and also to decrease the chemo-attraction and recruitment of immune cells to the inflammatory site. In addition to this, resveratrol was shown to possess anti-VEGF effects and to inhibit the proliferation and migration of vascular endothelial cells. Resveratrol has the potential to be used in a range of human ocular diseases and conditions, based on animal models and in vitro experiments.

This review presents recent evidence implicating microRNAs (miRNAs) in the beneficial effects of resveratrol (trihydroxystilbene), a nonflavonoid plant polyphenol, with emphasis on its anti-inflammatory effects. Many diseases and pathologies have been linked, directly or indirectly, to inflammation. These include infections, injuries, atherosclerosis, diabetes mellitus, obesity, cancer, osteoarthritis, age-related macular degeneration, demyelination, and neurodegenerative diseases. Resveratrol can both decrease the secretion of proinflammatory cytokines (e.g., IL-6, IL-8, and TNF-α) and increase the production of anti-inflammatory cytokines; it also decreases the expression of adhesion proteins (e.g., ICAM-1) and leukocyte chemoattractants (e.g., MCP-1). Resveratrol's primary targets appear to be the transcription factors AP-1 and NF-κB, as well as the gene COX2. Although no mechanistic link between any particular miRNA and resveratrol has been identified, resveratrol effects depend at least in part upon the modification of the expression of a variety of miRNAs that can be anti-inflammatory (e.g., miR-663), proinflammatory (e.g., miR-155), tumor suppressing (e.g., miR-663), or oncogenic (e.g., miR-21).

In this study, we examined the mechanism of action of the novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor 5-benzylidene-hydantoin UPR1024, whose structure was designed to interact at the ATP-binding site of EGFR. The compound had antiproliferative and proapoptotic effects when tested on the non -small cell lung cancer cell line A549. The growth inhibitory effect was associated with an accumulation of the cells in the S phase of the cell cycle. Moreover, UPR1024 induced significant level of DNA strand breaks associated with increased expression of p53 and p21 WAF1 proteins, suggesting an additive mechanism of action. The presence of wild-type p53 improved the drug efficacy, although the effect was also detectable in p53 null cells. We also noted apoptotic cell death after treatment with UPR1024 at concentrations above 10 Mmol/L for >24 h, with involvement of both the extrinsic and intrinsic pathways. The present data show that UPR1024 may be considered a combimolecule capable of both blocking EGFR tyrosine kinase activity and inducing genomic DNA damage. UPR1024 or its derivatives might serve as a basis for development of drugs for the treatment of lung cancer in patients resistant to classic tyrosine kinase inhibitors. [Mol Cancer Ther 2008;7(2):361 -70]