Targeting PI3K/Akt signal transduction for cancer therapy

Signal Transduction and Targeted Therapy, Год журнала: 2021, Номер 6(1)

Опубликована: Дек. 16, 2021

Abstract The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a crucial role in various cellular processes and is aberrantly activated cancers, contributing to the occurrence progression of tumors. Examining upstream downstream nodes this could allow full elucidation its function. Based on accumulating evidence, strategies targeting major components might provide new insights for cancer drug discovery. Researchers have explored use some inhibitors block survival pathways. However, because oncogenic PI3K activation occurs through mechanisms, clinical efficacies these are limited. Moreover, accompanied by development therapeutic resistance. Therefore, involving other treatments combination solve dilemma. In review, we discuss roles PI3K/Akt phenotypes, review current statuses different inhibitors, introduce therapies consisting signaling conventional therapies. information presented herein suggests that cascading pathway, either alone or with therapies, most effective treatment strategy cancer.

Язык: Английский

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Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Pharmacological Reviews, Год журнала: 2018, Номер 70(2), С. 348 - 383

Опубликована: Март 5, 2018

Systems medicine has a mechanism-based rather than symptom- or organ-based approach to disease and identifies therapeutic targets in nonhypothesis-driven manner. In this work, we apply transcription factor nuclear (erythroid-derived 2)–like 2 (NRF2) by cross-validating its position protein–protein interaction network (the NRF2 interactome) functionally linked cytoprotection low-grade stress, chronic inflammation, metabolic alterations, reactive oxygen species formation. Multiscale analysis of these molecular profiles suggests alterations expression activity as common mechanism subnetwork diseases diseasome). This joins apparently heterogeneous phenotypes such autoimmune, respiratory, digestive, cardiovascular, metabolic, neurodegenerative diseases, along with cancer. Importantly, matches confirms silico several applications for NRF2-modulating drugs validated vivo at different phases clinical development. Pharmacologically, their profile is diverse electrophilic dimethyl fumarate, synthetic triterpenoids like bardoxolone methyl sulforaphane, DNA–protein inhibitors, even registered metformin statins, which activate may be repurposed indications within the cluster phenotypes. Thus, represents one first fully embraced classic systems approaches facilitate both drug development repurposing focusing on set that appear mechanistically linked. The resulting drugome therefore rapidly advance surprising options subset diseases.

Язык: Английский

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Genetics, diagnosis and management of colorectal cancer (Review)

Oncology Reports, Год журнала: 2015, Номер 34(3), С. 1087 - 1096

Опубликована: Июль 3, 2015

Colorectal cancer (CRC) is the third most common type of worldwide and a leading cause death. Surgery represents mainstay treatment in early cases but often patients are primarily diagnosed an advanced stage disease sometimes also distant metastases present. Neoadjuvant therapy therefore needed drug resistance may influence response concur to recurrent disease. At molecular level, it very heterogeneous group diseases with about 30% hereditary or familial cases. During colorectal adenocarcinomas development, epithelial cells from gastrointestinal trait acquire sequential genetic epigenetic mutations specific oncogenes and/or tumour suppressor genes, causing CRC onset, progression metastasis. Molecular characterization associated gives valuable information prognosis therapy. Very diagnosis personalised care, as well better knowledge basis its onset progression, crucial obtain cure CRC. In this review, we describe updated genetics, current management pointing out extreme need for multidisciplinary approach achieve best results patient outcomes.

Язык: Английский

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Pivotal role of glycogen synthase kinase-3: A therapeutic target for Alzheimer's disease

European Journal of Medicinal Chemistry, Год журнала: 2015, Номер 107, С. 63 - 81

Опубликована: Окт. 24, 2015

Язык: Английский

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Targeting GSK3 and Associated Signaling Pathways Involved in Cancer

Cells, Год журнала: 2020, Номер 9(5), С. 1110 - 1110

Опубликована: Апрель 30, 2020

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine (S/T) protein kinase. Although GSK-3 originally was identified to have functions in regulation of glycogen synthase, it subsequently determined roles multiple normal biochemical processes as well various disease conditions. sometimes referred moonlighting due the substrates and which controls. Frequently, when phosphorylates proteins, they are targeted for degradation. often considered component PI3K/PTEN/AKT/GSK-3/mTORC1 pathway frequently phosphorylated by AKT regulates its inactivation. active human cancer hence, inactivated. Moreover, also interacts with WNT/β-catenin signaling β-catenin other proteins this targets GSK-3. can modify NF-κB activity expressed at high levels cells. Multiple pharmaceutical companies developed small molecule inhibitors suppress activity. In addition, natural products will This review focus on effects provide examples where these compounds were effective suppressing growth.

Язык: Английский

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Signal Transduction Pathways in Breast Cancer: The Important Role of PI3K/Akt/mTOR

Journal of Oncology, Год журнала: 2020, Номер 2020, С. 1 - 11

Опубликована: Март 9, 2020

Breast cancer is the with highest prevalence in women and number-one cause of mortality worldwide. Cell transduction a fundamental process development progression cancer. Modifications various cell signalling pathways promote tumour proliferation, progression, survival. The PI3K/Akt/mTOR pathway an example that, it involved growth, survival, motility, metabolism, immune response regulation. Activation this one main causes resistance to antitumour therapies. This makes crucial object study for understanding disease. Thus, may have role as potential therapeutic target, well prognostic diagnostic value, patients breast Despite existence selective inhibitors current clinical trials, cellular mechanisms are not yet known. present review aims understand state important disease paths that must be forged.

Язык: Английский

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Regulation of PD-L1: Emerging Routes for Targeting Tumor Immune Evasion

Frontiers in Pharmacology, Год журнала: 2018, Номер 9

Опубликована: Май 22, 2018

Immune checkpoint blockade therapies (ICBTs) targeting programmed cell death 1 (PD-1) and its ligand ligand-1 (PD-L1/B7-H1/CD274) have exhibited momentous clinical benefits durable responses in multiple tumor types. However, primary resistance is found considerable number of cancer patients, most responders eventually develop acquired to ICBT. To tackle these challenges, it essential understand how PD-L1 controlled by cells evade immune surveillance. Recent research has shed new light into the mechanisms regulation at genetic, epigenetic, transcriptional, translational posttranslational levels. In this work, we systematically discuss that control gene amplification, epigenetic alteration, transcription, subcellular transportation posttranscriptional modification cells. We further categorize regulations molecular PD-L1, including glycosylation, phosphorylation, ubiquitination, deubiquitination lysosomal degradation. These findings may provide routes for escape catalyze development small inhibitors addition existing antibody drugs.

Язык: Английский

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Proteomics, Post-translational Modifications, and Integrative Analyses Reveal Molecular Heterogeneity within Medulloblastoma Subgroups

Cancer Cell, Год журнала: 2018, Номер 34(3), С. 396 - 410.e8

Опубликована: Сен. 1, 2018

Язык: Английский

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Intracellular signaling pathway regulation of myelination and remyelination in the CNS

Experimental Neurology, Год журнала: 2016, Номер 283, С. 501 - 511

Опубликована: Март 5, 2016

Язык: Английский

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Acetyl-CoA metabolism in cancer

Nature reviews. Cancer, Год журнала: 2023, Номер 23(3), С. 156 - 172

Опубликована: Янв. 19, 2023

Few metabolites can claim a more central and versatile role in cell metabolism than acetyl coenzyme A (acetyl-CoA). Acetyl-CoA is produced during nutrient catabolism to fuel the tricarboxylic acid cycle essential building block for fatty isoprenoid biosynthesis. It also functions as signalling metabolite substrate lysine acetylation reactions, enabling modulation of protein response acetyl-CoA availability. Recent years have seen exciting advances our understanding normal physiology cancer, buoyed by new mouse models, vivo stable-isotope tracing approaches improved methods measuring acetyl-CoA, including specific subcellular compartments. Efforts target metabolic enzymes are advancing, with one therapeutic agent targeting synthesis receiving approval from US Food Drug Administration. In this Review, we give an overview regulation cancer relevance major pathways which participates. We further discuss recent tissues tumours potential these therapeutically. conclude commentary on emerging nodes that may impact biology.

Язык: Английский

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