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Despite significant advances, the eradication of cancer remains a clinical challenge which justifies the urgent exploration of additional therapeutic strategies such as immunotherapies. Human peripheral Vγ9Vδ2 T cells represent an attractive candidate subset for designing safe, feasible and effective adoptive T cell transfer-based therapies. However, following their infiltration within tumors, gd T cells are exposed to various regulating constituents and signals from the tumor microenvironment (TME), which severely alter their antitumor functions. Here, we show that TGF-b, whose elevated production in some solid tumors is linked to a poor prognosis, interferes with the antigenic activation of human Vγ9Vδ2 T cells in vitro. This regulatory cytokine strongly impairs their cytolytic activity, which is accompanied by the induction of particular phenotypic, transcriptomic and metabolic changes. Collectively, these observations provide information for better understanding and targeting the impact of TME components to regulate the antitumor activity of human T cell effectors. [ABSTRACT FROM AUTHOR]

Gamma/delta (γδ) T cells are innate-like immune effectors that are a critical component linking innate and adaptive immune responses. They are recognized for their contribution to tumor surveillance and fight against infectious diseases. γδ T cells are excellent candidates for cellular immunotherapy due to their unique properties to recognize and destroy tumors or infected cells. They do not depend on the recognition of a single antigen but rather a broad-spectrum of diverse ligands through expression of various cytotoxic receptors. In this manuscript, we review major characteristics of the most abundant circulating γδ subpopulation, Vδ2 T cells, their immunotherapeutic potential, recent advances in expansion protocols, their preclinical and clinical applications for several infectious diseases and malignancies, and how additional modulation could enhance their therapeutic potential. [ABSTRACT FROM AUTHOR]

There are a plethora of cancer causes and the road to fully understanding the carcinogenesis process remains a dream that keeps changing. However, a list of role players that are implicated in the carcinogens process is getting lengthier. Cholesterol is known as bad sterol that is heavily linked with cardiovascular diseases; however, it is also comprehensively associated with carcinogenesis. There is an extensive list of strategies that have been used to lower cholesterol; nevertheless, the need to find better and effective strategies remains vastly important. The role played by cholesterol in the induction of the carcinogenesis process has attracted huge interest in recent years. Phytochemicals can be dubbed as magic tramp cards that humans could exploit for lowering cancer-causing cholesterol. Additionally, the mechanisms that are regulated by phytochemicals can be targeted for anticancer drug development. One of the key role players in cancer development and suppression, Tumour Protein 53 (TP53), is crucial in regulating the biogenesis of cholesterol and is targeted by several phytochemicals. This minireview covers the role of p53 in the mevalonate pathway and how bioactive phytochemicals target the mevalonate pathway and promote p53-dependent anticancer activities. [ABSTRACT FROM AUTHOR]

Despite recent advances, the eradication of cancers still represents a challenge which justifies the exploration of additional therapeutic strategies such as immunotherapies, including adoptive cell transfers. Human peripheral Vγ9Vδ2 T cells, which constitute a major transitional immunity lymphocyte subset, represent attractive candidates because of their broad and efficient anti-tumor functions, as well as their lack of alloreactivity and easy handling. Vγ9Vδ2 T cells act like immune cell stress sensors that can, in a tightly controlled manner but through yet incompletely understood mechanisms, detect subtle changes of levels of phosphorylated metabolites of isoprenoid synthesis pathways. Consequently, various anti-tumor immunotherapeutic strategies have been proposed to enhance their reactivity and cytotoxicity, as well as to reduce the deleterious events. In this review, we expose these advances based on different strategies and their validation in preclinical models. Importantly, we next discuss advantages and limits of each approach, by highlighting the importance of the use of relevant preclinical model for evaluation of safety and efficacy. Finally, we propose novel perspectives and strategies that should be explored using these models for therapeutic improvements. [ABSTRACT FROM AUTHOR]

The traditional method of drug discovery process has been surpassed by a rational approach where computer-aided drug designing plays a vital role in the identification of leads from large compound databases. Further, natural products have an important role in drug discovery as these have been the source of most active ingredients of medicines. Herein, in silico structure- and ligand-based approaches have been applied to screen in-house IIIM natural product repository for Akt1 (serine/threonine protein kinases) which is a well-known therapeutic target for cancer due to its overexpression and preventing the cells from undergoing apoptosis. Combined ligand-based and structure-based strategies were applied on to the existing library comprising of about 700 pure natural products, and the compounds identified from screening were biologically evaluated for Akt1 inhibition using Akt1 kinase activity assay. Fourteen promising compounds showed significant inhibition at 500 nM through in vitro screening, and from them, eight were new for Akt1 inhibition. Through the MD studies of Akt1 with the most active compound IN00145, it was inferred that Lys179, Glu191, Glu228, Ala230, Glu234 and Asp292 are the important amino acid residues which provide stability to the Akt1-IN00145 complex. Lead optimization studies were also performed around the actives to design better and selective inhibitors for Akt1. The results emphasized the successful application of virtual screening to identify new Akt1 inhibitor scaffolds that can be developed into a drug candidate in drug discovery programme. [ABSTRACT FROM AUTHOR]

The p53 pathway is inactivated in the majority of human cancers. Although this perturbation frequently occurs through the mutation or deletion of p53 itself, there are other mechanisms that can attenuate the pathway and contribute to tumorigenesis. For example, overexpression of important p53 negative regulators, such as murine double minute 2 (MDM2) or murine double minute 4 (MDM4), epigenetic deregulation, or even alterations in TP53 mRNA splicing. In this work, we will review the different mechanisms of p53 pathway inhibition in cancer with special focus on multiple myeloma (MM), the second most common hematological malignancy, with low incidence of p53 mutations/deletions but growing evidence of indirect p53 pathway deregulation. Translational implications for MM and cancer prognosis and treatment are also reviewed. [ABSTRACT FROM AUTHOR]

Since its discovery nearly 40 years ago, p53 has ascended to the forefront of investigated genes and proteins across diverse research disciplines and is recognized most exclusively for its role in cancer as a tumor suppressor. Levine and Oren (2009) reviewed the evolution of p53 detailing the significant discoveries of each decade since its first report in 1979. In this review, we will highlight the emerging non-canonical functions and regulation of p53 in stem cells. We will focus on general themes shared among p53's functions in non-malignant stem cells and cancer stem-like cells (CSCs) and the influence of p53 on the microenvironment and CSC niche. We will also examine p53 gain of function (GOF) roles in stemness. Mutant p53 (mutp53) GOFs that lead to survival, drug resistance and colonization are reviewed in the context of the acquisition of advantageous transformation processes, such as differentiation and dedifferentiation, epithelial-to-mesenchymal transition (EMT) and stem cell senescence and quiescence. Finally, we will conclude with therapeutic strategies that restore wild-type p53 (wtp53) function in cancer and CSCs, including RING finger E3 ligases and CSC maintenance. The mechanisms by which wtp53 and mutp53 influence stemness in non-malignant stem cells and CSCs or tumor-initiating cells (TICs) are poorly understood thus far. Further elucidation of p53's effects on stemness could lead to novel therapeutic strategies in cancer research. [ABSTRACT FROM AUTHOR]

α-Helices often recognize their target proteins at protein--protein interfaces through more than one recognition face. This review describes the state-of-the-art in the design of non-peptidic α-helix mimetics that reproduce functionality from multiple faces of an α-helix. [ABSTRACT FROM AUTHOR]

It is widely accepted that epigenetic alterations are associated with different stages of tumour formation and progression in many cancers. Therefore, epigenetic abnormalities in cancers are emerging as important biomarkers and may have therapeutic potential. The polycomb repressive complex 2 (PRC2) is a key epigenetic regulator that catalyses trimethylation of lysine 27 on histone H3 (H3K27me3) via the histone methyltransferase, EZH2, which confers stemness and regulates differentiation during embryonic development. Given these roles of EZH2 and H3K27me3, plastic and dynamic features of cancer cells, especially cancer stem cells (CSCs), may be closely associated with this epigenetic mechanism. In addition, recent sequencing technology revealed that there are many recurrent mutations in polycomb-related genes, including EZH2, in different types of cancers. Therefore, researchers focused on targeting EZH2 as a novel cancer treatment and identified small compounds that inhibit EZH2 activity. Some of them are now under clinical trial in B-cell lymphoma. However, the underlying mechanisms by which PRC2 precisely regulate epigenetic alterations at certain genomic loci under different cellular conditions remain unclear. In this review, I focus on the recent advancements in EZH2 research, especially its dynamic regulation of epigenetic alterations in tumour cells, including the CSC population, and discuss perspectives and challenges for cancer treatment in the near future. [ABSTRACT FROM AUTHOR]

Angiogenesis refers to the process of remodeling the vascular tissue characterized by the branching out of a new blood vessel from a pre-existing vessel. Angiogenesis is particularly active during embryogenesis, while during adult life it is quiescent and limited to particular physiologic phenomena. Recently, the study of molecular mechanisms of angiogenesis has stirred renewed interest due to the recognition of the role played by angiogenesis in several pathologies of significant medical impact, such as cancer and cardiovascular disease, and due to the pharmacologic interest rising from the possibility of modulating these phenomena. Antibodies, peptides and small molecules targeting active endothelial cells represent an innovative tool in therapeutic and diagnostic fields. In this study, we reviewed the literature of peptide and peptidomimetics in angiogenesis and their potential applications. Two specific protein systems, namely the vascular endothelial growth factor and its receptor and integrins, will be discussed in detail. [ABSTRACT FROM AUTHOR]

Disruption of epigenetic processes to eradicate tumor cells is among the most promising interventions for cancer control. EZH2 (Enhancer of zeste homolog 2), a catalytic component of polycomb repressive complex 2 (PRC2), methylates lysine 27 of histone H3 to promote transcriptional silencing and is an important drug target for controlling cancer via epigenetic processes. In the present study, we have developed various predictive models for modeling the inhibitory activity of EZH2. Binary and multiclass models were built using SVM, random forest and XGBoost methods. Rigorous validation approaches including predictiveness curve, Y-randomization and applicability domain (AD) were employed for evaluation of the developed models. Eighteen descriptors selected from Boruta methods have been used for modeling. For binary classification, random forest and XGBoost achieved an accuracy of 0.80 and 0.82, respectively, on external test set. Contrastingly, for multiclass models, random forest and XGBoost achieved an accuracy of 0.73 and 0.75, respectively. 500 Y-randomization runs demonstrate that the models were robust and the correlations were not by chance. Evaluation metrics from predictiveness curve show that the selected eighteen descriptors predict active compounds with total gain (TG) of 0.79 and 0.59 for XGBoost and random forest, respectively. Validated models were further used for virtual screening and molecular docking in search of potential hits. A total of 221 compounds were commonly predicted as active with above the set probability threshold and also under the AD of training set. Molecular docking revealed that three compounds have reasonable binding energy and favorable interactions with critical residues in the active site of EZH2. In conclusion, we highlighted the potential of rigorously validated models for accurately predicting and ranking the activities of lead molecules against cancer epigenetic targets. The models presented in this study represent the platform for development of EZH2 inhibitors. [ABSTRACT FROM AUTHOR]