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Targeting pancreatic cancer immune evasion by inhibiting histone deacetylases.

The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development. Regardless, it is not uncommon that cancerous cells can intelligently acquire abilities to bypass the antitumor immune responses, thus allowing continuous tumor growth and development. Immune evasion has emerged as a significant factor contributing to the progression and immune resistance of pancreatic cancer. Compared with other cancers, pancreatic cancer has a tumor microenvironment that can resist most treatment modalities, including emerging immunotherapy. Sadly, the u

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… The KRAS GTPase switches between being bound to guanosine diphosphate, GDP (inactive state) and being bound to guanosine triphosphate, GTP (active state)[ 10 ]. In cancer development, missense mutations cause RAS to be persistently bound to GTP allowing an unlimited cellular proliferation. …

Экспериментальные и клинические исследования фармакологических действий рода ахиллия: всеобъемлющий и обновленный обзор.

ЦЕЛЬ: Виды рода Ахиллеа (от семейства Compositae или Asteraceae) широко используются для их многочисленных фармакологических свойств. В настоящем документе рассматриваются фармакологические действия и их возможные основополагающие молекулярные механизмы, о которых сообщается в отношении различных видов ахиллы. МАТЕРИАЛЫ И МЕТОДЫ: использовались различные базы данных, включая PubMed, Science Direct и Scopus. Результаты: Для этих растений были продемонстрированы эффекты иммуноспрепрессии, против воспламенения и против окислителей. Кроме того, было продемонстрировано, что эти растения оказывают н

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… AC: adenylyl cyclase; ATP: adenosine triphosphate; cAMP: cyclic adenosine monophosphate; Ca ++ : calcium; DAG: diacylglycerol; GTP: guanosine triphosphate; IP3: inositol trisphosphate; PIP2: phosphatidylinositol biphosphate; PKA: protein kinase A; PKC: protein kinase C; and PLC: phospholipase C. …

Cancer Therapy and Exercise Intolerance: The Heart Is But a Part: JACC: CardioOncology State-of-the-Art Review.

The landscape of cancer therapeutics is continually evolving, with successes in improved survivorship and reduced disease progression for many patients with cancer. Improved cancer outcomes expose competing comorbidities, some of which may be exacerbated by cancer therapies. The leading cause of disability and death for many early-stage cancers is cardiovascular disease (CVD), which is often attributed to direct or indirect cardiac injury from cancer therapy. In this review, the authors propose that toxicities related to conventional and novel cancer therapeutics should be considered beyond th

DNA Damaging Drugs

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HDAC6-an Emerging Target Against Chronic Myeloid Leukemia?

Imatinib became the standard treatment for chronic myeloid leukemia (CML) about 20 years ago, which was a major breakthrough in stabilizing the pathology and improving the quality of life of patients. However, the emergence of resistance to imatinib and other tyrosine kinase inhibitors leads researchers to characterize new therapeutic targets. Several studies have highlighted the role of histone deacetylase 6 (HDAC6) in various pathologies, including cancer. This protein effectively intervenes in cellular activities by its primarily cytoplasmic localization. In this review, we will discuss the

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… It also has a domain of homology to the protein DBL [guanosine diphosphate exchange factor (GDP) in guanosine triphosphate (GTP)], a domain of pleckstrin homology (PH), a C2 domain for binding of calcium-dependent phospholipids, and finally a GTPase (GTPase activating protein) domain (GTPase hydrolysis … Abi: Abelson interactor; BAP-1: breakpoint cluster region-associated protein 1; Cbl: Casitas-B-lineage protein; CK: casein kinase; CrkL: Crk like protein; Dok: docking protein; GAP: guanosine triphosphate (GTP)ase-activating proteins; GCKR: germinal-center kinase related protein; Grb2: growth factor …

Lomitapide repurposing for treatment of malignancies: A promising direction.

The development of novel drugs from basic science to clinical practice requires several years, much effort, and cost. Drug repurposing can promote the utilization of clinical drugs in cancer therapy. Recent studies have shown the potential effects of lomitapide on treating malignancies, which is currently used for the treatment of familial hypercholesterolemia. We systematically review possible functions and mechanisms of lomitapide as an anti-tumor compound, regarding the aspects of apoptosis, autophagy, and metabolism of tumor cells, to support repurposing lomitapide for the clinical treatme

ENPP1/CD203a-targeting heavy-chain antibody reveals cell-specific expression on human immune cells.

ENPP1/CD203a is a membrane-bound ectonucleotidase capable of hydrolyzing ATP, cGAMP and other substrates. Its enzymatic activity plays an important role in the balance of extracellular adenine nucleotides and the modulation of purinergic signaling, in soft tissue calcification, and in the regulation of the cGAS/STING pathway. However, a detailed analysis of ENPP1 surface expression on human immune cells has not been performed. Here, we selected VHH domains from human ENPP1-immunized alpacas to generate heavy-chain antibodies targeting ENPP1, and analyzed cell surface expression on all circulat

Декодирование GPCR, сигнализирующее перепрограммирование рака: молекулярные механизмы и терапевтические последствия.

G белковые рецепторы (GPCR) представляют собой крупнейшую мембранную группу рецепторов в геноме человека и служат ключевыми регуляторами клеточного сигнала, гомеостаза и фармакологической реакции. Помимо их классической роли в посредничестве внеклеточной стимуляции по зависящим от G-протеина и независимым путям, которые играют ключевую роль при помощи GPCR сигнальных путей, включая CAMP-PKA/EPAC, IP3/PLC, PI3K/Akt/mTOR и ERK/MAPK cascades, в вождении онкогенного распространения, апоптоза и метастаза. Кроме того, ГПХР замешаны в опухоли с помощью различных молекулярных механизмов, в рамках кото

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… This process is accelerated by regulators of G protein signaling (RGS) proteins that turn off the activated Gα-GTP by facilitating the GTPase that hydrolyzes GTP (guanosine triphosphate) to GDP (guanosine diphosphate) (O’Hayre et al. 2013 ). …

Drug repurposing approach to fight COVID-19.

Currently, there are no treatment options available for the deadly contagious disease, coronavirus disease 2019 (COVID-19). Drug repurposing is a process of identifying new uses for approved or investigational drugs and it is considered as a very effective strategy for drug discovery as it involves less time and cost to find a therapeutic agent in comparison to the de novo drug discovery process. The present review will focus on the repurposing efficacy of the currently used drugs against COVID-19 and their mechanisms of action, pharmacokinetics, dosing, safety, and their future perspective. R

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… Ribavirin in its monophosphate form inhibits host inosine monophosphate dehydrogenase (IMPDH) enzyme that controls intracellular guanosine triphosphate (GTP) pools [ 52 ]. Exhaustion of intracellular GTP pool indirectly inhibits viral RDRP enzyme. It also interferes with mRNA capping. …

Oncogenes: The Passport for Viral Oncolysis Through PKR Inhibition.

The transforming properties of oncogenes are derived from gain-of-function mutations, shifting cell signaling from highly regulated homeostatic to an uncontrolled oncogenic state, with the contribution of the inactivating mutations in tumor suppressor genes P53 and RB, leading to tumor resistance to conventional and target-directed therapy. On the other hand, this scenario fulfills two requirements for oncolytic virus infection in tumor cells: inactivation of tumor suppressors and presence of oncoproteins, also the requirements to engage malignancy. Several of these oncogenes have a negative i

ITF6475, a New Histone Deacetylase 6 Inhibitor, Prevents Painful Neuropathy Induced by Paclitaxel.

Chemotherapy-induced peripheral neuropathy remains a significant side effect of cancer treatment, often requiring dose reductions or even discontinuation of therapy. Paclitaxel (PTX), a widely used chemotherapeutic agent for solid tumors, is particularly neurotoxic, and no effective treatment exists for paclitaxel-induced peripheral neuropathy (PIPN). Histone deacetylases (HDACs) are enzymes that remove acetyl groups from histone and non-histone proteins, including transcription factors and cytoskeletal components. This study evaluates the HDAC6 inhibitor ITF6475 for its potential to prevent P

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… Abbreviations The following abbreviations are used in this manuscript: CIPN | chemotherapy-induced neuropathy DMSO | dimethyl sulfoxide EDTA | ethylenediaminetetraacetic acid GTPase | guanosine triphosphate hydrolase HDAC | histone deacetylase IENF | intraepidermal nerve fibers i.v. | intravenous …

Beyond DNA Damage: Exploring the Immunomodulatory Effects of Cyclophosphamide in Multiple Myeloma.

The alkylating agent cyclophosphamide has been used in the treatment of multiple myeloma for over 60 years. At low doses, cyclophosphamide also has significant immunomodulatory activity, which can be used to modify the immunosuppressive tumor microenvironment in order to augment responses to existing therapies. Immune-mediated therapies are becoming more widespread in modern approaches to myeloma treatment. In this review, we discuss the effects cyclophosphamide has on the immune system, and how it can be used synergistically with other treatment modalities including the immunomodulatory agent

Molecular glue degrader for tumor treatment.

Targeted Protein Degradation (TPD) represented by Proteolysis-Targeting Chimeras (PROTAC) is the frontier field in the research and development of antitumor therapy, in which oral drug HP518 Receives FDA Proceed Authorization for its IND Application for Prostate Cancer Treatment. Recently, molecular glue, functioning via degradation of the target protein is emerging as a promising modality for the development of therapeutic agents, while exhibits greater advantages over PROTAC, including improved efficiency, resistance-free properties, and the capacity to selectively target "undruggable" prote

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… Most of these inhibitors target the inactive form of KRAS G12C, bound to guanosine diphosphate (GDP), which exhibits slow onset and rapid resistance ( 147 , 148 ).Researchers shifted their focus to the active state of KRAS G12C bound to guanosine triphosphate (GTP). …

Воздействие фингозина-1-фосфатных модуляторов рецепторов на ремиелионацию при множественном склерозе: данные экспериментов in vitro, модели животных и исследования человека.

Сфингосин-1-фосфат (S1P) является классом терапевтических агентов, используемых для лечения множественного склероза (MS). В настоящее время Управление по контролю за продуктами питания и лекарствами/Европейское медицинское агентство (FDA/EMA) утвердило четыре модулятора S1P: финголимод, сипонимоз, понизимод и озанимод. Помимо их хорошо зарекомендовавших себя иммунодуляционных свойств, накапливаемые данные свидетельствуют о том, что эти молекулы оказывают прямое воздействие на клетки потомков олигодендроцитов (ОРК) и зрелые олигодендроциты, содействуя ремонту миелина с помощью различных механиз

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… Upon ligand binding, S1P receptors activate multiple intracellular pathways, including mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (PI3K)/Akt, and Rho guanosine triphosphate-phosphohydrolase (GTPases), which collectively regulate cell survival, proliferation, migration, and differentiation …

The 'speck'-tacular oversight of the NLRP3-pyroptosis pathway on gastrointestinal inflammatory diseases and tumorigenesis.

The NLRP3 inflammasome is an intracellular sensor and an essential component of the innate immune system involved in danger recognition. An important hallmark of inflammasome activation is the formation of a single supramolecular punctum, known as a speck, per cell, which is the site where the pro-inflammatory cytokines IL-1β and IL-18 are converted into their bioactive form. Speck also provides the platform for gasdermin D protein activation, whose N-terminus domain perforates the plasma membrane, allowing the release of mature cytokines alongside with a highly inflammatory form of cell death

Opportunities and Challenges of Small Molecule Induced Targeted Protein Degradation.

Proteolysis targeting chimeras (PROTAC) represents a new type of small molecule induced protein degradation technology that has emerged in recent years. PROTAC uses bifunctional small molecules to induce ubiquitination of target proteins and utilizes intracellular proteasomes for chemical knockdown. It complements the gene editing and RNA interference for protein knockdown. Compared with small molecule inhibitors, PROTAC has shown great advantages in overcoming tumor resistance, affecting the non-enzymatic function of target proteins, degrading undruggable targets, and providing new rapid and

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… KRAS is one of the most frequently mutated oncogenes, which can be activated through a variety of ways and cause tumor development, such as binding to guanosine triphosphate and activated by cell surface receptors. … The mutated codon interacts with guanosine triphosphate hydrolase, which activates KRAS and ultimately leads to tumorigenesis. …

Evidence for reciprocal network interactions between injured hearts and cancer.

Heart failure (HF) and cancer are responsible for 50% of all deaths in middle-aged people. These diseases are tightly linked, which is supported by recent epidemiological studies and case control studies, demonstrating that HF patients have a higher risk to develop cancer such as lung and breast cancer. For HF patients, a one-size-fits-all clinical management strategy is not effective and patient management represents a major economical and clinical burden. Anti-cancer treatments-mediated cardiotoxicity, leading to HF have been extensively studied. However, recent studies showed that even befo

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… For example, the RAS family of small Guanosine Triphosphate (GTP)-binding proteins (G proteins) plays a key role in intracellular signal transduction required for normal cardiac growth, development of hypertrophic cardiomyopathy and HF as well as cancer ( 74 ). …

Antimitotic drugs in the treatment of cancer.

Cancer is a complex disease since it is adaptive in such a way that it can promote proliferation and invasion by means of an overactive cell cycle and in turn cellular division which is targeted by antimitotic drugs that are highly validated chemotherapy agents. However, antimitotic drug cytotoxicity to non-tumorigenic cells and multiple cancer resistance developed in response to drugs such as taxanes and vinca alkaloids are obstacles faced in both the clinical and basic research field to date. In this review, the classes of antimitotic compounds, their mechanisms of action and cancer cell res

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… These compounds bind to β-tubulin close to the guanosine triphosphate (GTP)-binding sites (the vinca domain) at the β-α-tubulin heterodimers interface [ 20 ]. …

Потенциальное терапевтическое воздействие ибудиластной и ретиновой кислоты на поведенческие и биохимические изменения в мышечном мозге.

Ibudilast (IBD) — новый препарат, выпущенный в качестве лекарства от множественных склерозов (MS). Ретиноиновая кислота (RA), являющаяся метаболитом витамина А, известна своими прорегенеративными и антивоспалительными свойствами, поэтому она была предложена в качестве дополнительного метода лечения для MS. Цель этого исследования заключается в изучении терапевтического воздействия RA и IBD на модели мышей, вызываемые кухонной зоной (CPZ). Seventy-two Швейцарские мыши-альбино (SWR/J) были разделены на two контроль за основными группами (n = 18); нормальная чау и CPZ (n = 54); 0.25% CPZ, смешанн

Purinergic Signalling: Therapeutic Developments.

Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990's when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and the