Ricerc@Sapienza

Purpose: Alteration in cell death is a hallmark of cancer. A functional role regulating survival, apoptosis, and necroptosis has been attributed to RIP1/3 complexes.Experimental Design: We have investigated the role of RIP1 and the effects of MC2494 in cell death induction, using different methods as flow cytometry, transcriptome analysis, immunoprecipitation, enzymatic assays, transfections, mutagenesis, and in vivo studies with different mice models.Results: Here, we show that RIP1 is highly expressed in cancer, and we define a novel RIP1/3-SIRT1/2-HAT1/4 complex.

Recently, despite the great success achieved by the so-called "magic bullets" in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of "molecular network active compounds," embracing the related polypharmacology approach.

Numerous and different types of cancers possess the dysregulation of the mevalonate pathway as a common feature. Statins, traditionally applied in cardiovascular diseases to reduce lipid levels, subsequently have been discovered to exhibit anti-cancer activities also. Indeed, statins influence proliferation, migration, and survival of cancer cells by regulating crucial signaling proteins, such as Rho, Ras, and Rac.

Sirtuins are NAD+-dependent deacylases that play crucial roles in the regulation of cellular metabolism, and as a result, are implicated in several diseases. The mitochondrial sirtuin Sirt4, for a long time considered as mainly a mono-ADP-ribosyltransferase, recently has shown a robust deacylase activity in addition to the already accepted substrate-dependent lipoamidase and deacetylase properties.

The involvement of sirtuins (SIRTs) in modulating metabolic and stress response pathways is attracting growing scientific interest. Some SIRT family members are located in mitochondria, dynamic organelles that perform several crucial functions essential for eukaryotic life. Mitochondrial dysfunction has emerged as having a key role in a number of human diseases, including cancer. Here, we investigated mitochondrial damage resulting from treatment with a recently characterized pan-SIRT inhibitor, MC2494.

Introduction: In recent years, sirtuins (SIRTs) gained an increasing consideration because of their multiple key roles in several biological settings such as the regulation of transcription, energetic metabolism, cell cycle progression and cytodifferentiation, apoptosis, neuro- and cardio-protection, inflammation, cancer onset and progression. Since there is mounting evidence in favour of potential therapeutic applications of SIRT modulators in various age-related disorders, the search about them is quite active.

Tubulin is the primary target of an ever growing number of natural, semisynthetic and synthetic products as potential anticancer agents. The mechanisms of interaction of these molecules with tubulin are varied. These drug classes have shown to inhibit effectively several cancer types with IC50 from midmicromolar to low nanomolar concentrations. However, some limiting obstacles still remain, such as the development of multidrug resistance and cytotoxicity.

Since 2000, the histone methyltransferases that catalyze the methylation of a number of histone and nonhistone substrates have been discovered. A growing body of literature is indicating that lysine methyltransferases (KMTs) play a crucial role for transcriptional regulation and are involved in cancer and. various other human diseases, thus being of high interest as potential therapeutic targets.

Sirtuins, a family of nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacetylases, are promising targets for anticancer treatment. Recently, we characterized a novel pan-sirtuin (SIRT) inhibitor, MC2494, displaying antiproliferative effects and able to induce death pathways in several human cancer cell lines and decrease tumor growth in vivo.

Cancer is considered a multifactorial pathology, whose understanding involves genomic and epigenomic studies supplemented by biochemical, biological, molecular, and epidemiological data. Current cancer research strategies are based on the paradigm of “targeted” therapies. Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules (“molecular targets”) that are involved in growth, progression, and spread of cancer.