Current Drug Targets - Volume 20, Issue 7, 2019

Background: Cellular senescence is generally understood as a permanent cell cycle arrest stemming from different causes. The mechanism of cellular senescence-induced cell cycle arrest is complex, involving interactions between telomere shortening, inflammations and cellular stresses. In recent years, a growing number of studies have revealed that cellular senescence could mediate the cancer progression of neighboring cells, but this idea is controversial and contradictory evidence argues that cellular senescence also contributes to tumor suppression. Objective: Given that the complicated role of senescence in various physiological and pathological scenarios, we try to clarify the precise contribution role of cellular senescence to tumor progression. Methods: Search for the information in a large array of relevant articles to support our opinion. Results: We discuss the relatively widespread occurrence of cellular senescence in cancer treatment and identify the positive and negative side of senescence contributed to tumor progression. Conclusion: We argue that the availability of pro-senescence therapy could represent as a promising regimen for managing cancer disease, particularly with regard to the poor clinical outcome obtained with other anticancer therapies.

Background: Cyclin-dependent kinase 2 (CDK2) has been studied due to its role in the cell-cycle progression. The elucidation of the CDK2 structure paved the way to investigate the molecular basis for inhibition of this enzyme, with the coordinated efforts combining crystallography with functional studies. Objective: Our goal here is to review recent functional and structural studies directed to understanding the role of CDK2 in cancer and senescence. Methods: There are over four hundreds of crystallographic structures available for CDK2, many of them with binding affinity information. We use this abundance of data to analyze the essential features responsible for the inhibition of CDK2 and its function in cancer and senescence. Results: The structural and affinity data available CDK2 makes it possible to have a clear view of the vital CDK2 residues involved in molecular recognition. A detailed description of the structural basis for ligand binding is of pivotal importance in the design of CDK2 inhibitors. Our analysis shows the relevance of the residues Leu 83 and Asp 86 for binding affinity. The recent findings revealing the participation of CDK2 inhibition in senescence open the possibility to explore the richness of structural and affinity data for a new era in the development of CDK2 inhibitors, targeting cellular senescence. Conclusion: Here, we analyzed structural information for CDK2 in combination with inhibitors and mapped the molecular aspects behind the strongest CDK2 inhibitors for which structures and ligandbinding affinity data were available. From this analysis, we identified the significant intermolecular interactions responsible for binding affinity. This knowledge may guide the future development of CDK2 inhibitors targeting cancer and cellular senescence.

Background: Heat shock proteins (HSPs) are predominant molecular chaperones which are actively involved in the protein folding; which is essential in protecting the structure and functioning of proteins during various stress conditions. Though HSPs have important physiological roles, they have been well known for their roles in various pathogenic conditions such as carcinogenesis; however, limited literature has consolidated its potential as an anti-metastatic drug target. Objectives: The present review outlines the role of different HSPs on cancer progression and metastasis; possible role of HSP inhibitors as anti-neoplastic agents is also discussed. Methods: The data were collected from PubMed/Medline and other reputed journal databases. The literature that was too old and had no significant role to the review was then omitted. Results: Despite their strong physiological functions, HSPs are considered as good markers for cancer prognosis and diagnosis. They have control over survival, proliferation and progression events of cancer including drug resistance, metastasis, and angiogenesis. Since, neoplastic cells are more dependent on HSPs for survival and proliferation, the selectivity and specificity of HSP-targeted cancer drugs remain high. This has made various HSPs potential clinical and experimental targets for cancer prevention. An array of HSP inhibitors has been in trials and many others are in experimental conditions as anticancer and anti-metastatic agents. Several natural products are also being investigated for their efficacy for anticancer and anti-metastatic agents by modulating HSPs. Conclusion: Apart from their role as an anticancer drug target, HSPs have shown to be promising targets for the prevention of cancer progression. Extensive studies are required for the use of these molecules as anti-metastatic agents. Further studies in this line may yield specific and effective antimetastatic agents.

Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that may play an important role in the evolution of cancers, due to their effects on cancer cell metabolism. Statins affect several potential pathways, including cell proliferation, angiogenesis, apoptosis and metastasis. The number of trials assessing the putative clinical benefits of statins in cancer is increasing. Currently, there are several trials listed on the global trial identifier website clinicaltrials.gov. Given the compelling evidence from these trials in a variety of clinical settings, there have been calls for a clinical trial of statins in the adjuvant gastrointestinal cancer setting. However, randomized controlled trials on specific cancer types in relation to statin use, as well as studies on populations without a clinical indication for using statins, have elucidated some potential underlying biological mechanisms, and the investigation of different statins is probably warranted. It would be useful for these trials to incorporate the assessment of tumour biomarkers predictive of statin response in their design. This review summarizes the recent preclinical and clinical studies that assess the application of statins in the treatment of gastrointestinal cancers with particular emphasize on their association with cancer risk.

Brain edema primarily occurs as a consequence of various cerebral injuries including ischemic stroke. Excessive accumulation of brain water content causes a gradual expansion of brain parenchyma, decreased blood flow and increased intracranial pressure and, ultimately, cerebral herniation and death. Current clinical treatment for ischemic edema is very limited, therefore, it is urgent to develop novel treatment strategies. Mounting evidence has demonstrated that AQP4, a water channel protein, is closely correlated with brain edema and could be an optimal therapeutic target for the reduction of ischemic brain edema. AQP4 is prevalently distributed in the central nervous system, and mainly regulates water flux in brain cells under normal and pathological conditions. This review focuses on the underlying mechanisms of AQP4 related to its dual role in edema formation and elimination.

An emerging crisis of antibiotic resistance for microbial pathogens is alarming all the nations, posing a global threat to human health. The production of the metallo-β-lactamase enzyme is the most powerful strategy of bacteria to produce resistance. An efficient way to combat this global health threat is the development of broad/non-specific type of metallo-β-lactamase inhibitors, which can inhibit the different isoforms of the enzyme. Till date, there are no clinically active drugs against metallo- β-lactamase. The lack of efficient drug molecules against MBLs carrying bacteria requires continuous research efforts to overcome the problem of multidrug-resistance bacteria. The present review will discuss the clinically potent molecules against different variants of B1 metallo-β-lactamase.

Owning the high incidence and disability rate in the past decades, to be expected, cardiovascular diseases (CVDs) have become one of the leading death causes worldwide. Currently, induced pluripotent stem cells (iPSCs), with the potential to form fresh myocardium and improve the functions of damaged hearts, have been studied widely in experimental CVD therapy. Moreover, iPSC-derived cardiomyocytes (CMs), as novel disease models, play a significant role in drug screening, drug safety assessment, along with the exploration of pathological mechanisms of diseases. Furthermore, a lot of studies have been carried out to clarify the biological basis of iPSCs and its derived cells in the treatment of CVDs. Their molecular mechanisms were associated with release of paracrine factors, regulation of miRNAs, mechanical support of new tissues, activation of specific pathways and specific enzymes, etc. In addition, a few small chemical molecules and suitable biological scaffolds play positive roles in enhancing the efficiency of iPSC transplantation. This article reviews the development and limitations of iPSCs in CVD therapy, and summarizes the latest research achievements regarding the application of iPSCs in CVDs.

Pain is a complex multidimensional concept that facilitates the initiation of the signaling cascade in response to any noxious stimuli. Action potential generation in the peripheral nociceptor terminal and its transmission through various types of nociceptors corresponding to mechanical, chemical or thermal stimuli lead to the activation of receptors and further neuronal processing produces the sensation of pain. Numerous types of receptors are activated in pain sensation which vary in their signaling pathway. These signaling pathways can be regarded as a site for modulation of pain by targeting the pain transduction molecules to produce analgesia. On the basis of their anatomic location, transient receptor potential ion channels (TRPV1, TRPV2 and TRPM8), Piezo 2, acid-sensing ion channels (ASICs), purinergic (P2X and P2Y), bradykinin (B1 and B2), α-amino-3-hydroxy-5- methylisoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMDA), metabotropic glutamate (mGlu), neurokinin 1 (NK1) and calcitonin gene-related peptide (CGRP) receptors are activated during pain sensitization. Various inhibitors of TRPV1, TRPV2, TRPM8, Piezo 2, ASICs, P2X, P2Y, B1, B2, AMPA, NMDA, mGlu, NK1 and CGRP receptors have shown high therapeutic value in experimental models of pain. Similarly, local inhibitory regulation by the activation of opioid, adrenergic, serotonergic and cannabinoid receptors has shown analgesic properties by modulating the central and peripheral perception of painful stimuli. This review mainly focused on various classes of nociceptors involved in pain transduction, transmission and modulation, site of action of the nociceptors in modulating pain transmission pathways and the drugs (both clinical and preclinical data, relevant to targets) alleviating the painful stimuli by exploiting nociceptor-specific channels and receptors.

Prostate cancer is malignant cancer leading to high mortality in the male population. The existence of suppressive cells referred to as tumor-associated macrophages (TAM) is a major obstacle in prostate cancer immunotherapy. TAMs contribute to the immunosuppressive microenvironment that promotes tumor growth and metastasis. In fact, they are main regulators of the complicated interactions between tumor and surrounding microenvironment. M2 macrophages, as a type of TAMs, are involved in the growth and progression of prostate cancer. Recently, they have gained remarkable importance as therapeutic candidates for solid tumors. In this review, we will discuss the roles of M2 macrophages and worth of their potential targeting in prostate cancer treatment. In the following, we will introduce important factors resulting in M2 macrophage promotion and also experimental therapeutic agents that may cause the inhibition of prostate cancer tumor growth.