Targeting the PI3K/Akt/mTOR Pathway in Hepatocellular Carcinoma

Biomedicines, Год журнала: 2021, Номер 9(11), С. 1639 - 1639

Опубликована: Ноя. 8, 2021

Despite advances in the treatment of cancers through surgical procedures and new pharmaceuticals, hepatocellular carcinoma (HCC) remains challenging as reflected by low survival rates. The PI3K/Akt/mTOR pathway is an important signaling mechanism that regulates cell cycle, proliferation, apoptosis, metabolism. Importantly, deregulation leading to activation common HCC hence subject intense investigation focus current therapeutics. In this review article, we consider role pathogenesis HCC, focusing on its downstream effectors such glycogen synthase kinase-3 (GSK-3), cAMP-response element-binding protein (CREB), forkhead box O (FOXO), murine double minute 2 (MDM2), p53, nuclear factor-κB (NF-κB), cellular processes lipogenesis autophagy. addition, provide update ongoing clinical development agents targeting for treatments.

Язык: Английский

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Oxidative stress in intervertebral disc degeneration: Molecular mechanisms, pathogenesis and treatment

Cell Proliferation, Год журнала: 2023, Номер 56(9)

Опубликована: Март 13, 2023

Abstract Low back pain (LBP) is a leading cause of labour loss and disability worldwide, it also imposes severe economic burden on patients society. Among symptomatic LBP, approximately 40% caused by intervertebral disc degeneration (IDD). IDD the pathological basis many spinal degenerative diseases such as herniation stenosis. Currently, therapeutic approaches for mainly include conservative treatment surgical treatment, neither which can solve problem from root terminating process (IVD). Therefore, further exploring pathogenic mechanisms adopting targeted strategies one current research hotspots. complex pathophysiological processes IDD, oxidative stress considered main factor. The delicate balance between reactive oxygen species (ROS) antioxidants essential maintaining normal function survival IVD cells. Excessive ROS levels damage to macromolecules nucleic acids, lipids, proteins cells, affect cellular activities functions, ultimately lead cell senescence or death. This review discusses potential role in understand provides IDD.

Язык: Английский

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Pathogenesis and Current Treatment Strategies of Hepatocellular Carcinoma

Biomedicines, Год журнала: 2022, Номер 10(12), С. 3202 - 3202

Опубликована: Дек. 9, 2022

Hepatocellular carcinoma (HCC) is the most frequent liver cancer with high lethality and low five-year survival rates leading to a substantial worldwide burden for healthcare systems. HCC initiation progression are favored by different etiological risk factors including hepatitis B virus (HBV) C (HCV) infection, non-/and alcoholic fatty disease (N/AFLD), tobacco smoking. In molecular pathogenesis, endogenous alteration in genetics (TP53, TERT, CTNNB1, etc.), epigenetics (DNA-methylation, miRNA, lncRNA, dysregulation of key signaling pathways (Wnt/β-catenin, JAK/STAT, etc.) strongly contribute development HCC. The multitude complexity pathomechanisms also reflect difficulties tailored medical therapy Treatment options strictly dependent on tumor staging function, which structured updated Barcelona Clinic Liver Cancer classification system. Surgical resection, local ablative techniques, transplantation valid curative therapeutic early stages. For multifocal metastatic diseases, systemic recommended. While Sorafenib had been standalone first-line decades, recent developments led approval new treatment as well second-line treatment. Anti-PD-L1 directed combination therapies either anti-VEGF agents or anti-CTLA-4 active substances have implemented standard setting. However, data from clinical trials indicate responses specific regimens depending underlying pathogenesis hepatocellular cancer. Therefore, histopathological examinations re-emphasized current international guidelines addition standardized radiological diagnosis using contrast-enhanced cross-sectional imaging. this review, we emphasize knowledge carcinoma. On occasion, sequences advanced stages according recently system algorithm (first-, second-, third-line treatment) summarized. Furthermore, discuss novel precautional pre-therapeutic approaches vaccination, adoptive cell transfer, locoregional enhancement, non-coding RNA-based promising options. These treatments may prolong overall regard quality life function mainstay therapy.

Язык: Английский

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Aging, oxidative stress and degenerative diseases: mechanisms, complications and emerging therapeutic strategies

Biogerontology, Год журнала: 2023, Номер 24(5), С. 609 - 662

Опубликована: Июль 30, 2023

Язык: Английский

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Hepatocellular carcinoma: signaling pathways, targeted therapy, and immunotherapy

MedComm, Год журнала: 2024, Номер 5(2)

Опубликована: Фев. 1, 2024

Abstract Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a high mortality rate. It regarded as significant public health issue because of its complicated pathophysiology, metastasis, and recurrence rates. There are no obvious symptoms in early stage HCC, which often leads to delays diagnosis. Traditional treatment methods such surgical resection, radiotherapy, chemotherapy, interventional therapies have limited therapeutic effects for HCC patients or metastasis. With development molecular biology immunology, signaling pathways immune checkpoint were identified main mechanism progression. Targeting these molecules has become new direction HCC. At present, combination targeted drugs inhibitors first choice advanced patients. In this review, we mainly focus on cutting‐edge research corresponding therapy immunotherapy great significance comprehensively understand pathogenesis search potential targets, optimize strategies

Язык: Английский

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First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure

Cell, Год журнала: 2024, Номер 187(7), С. 1666 - 1684.e26

Опубликована: Март 1, 2024

Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases after extended resections, resulting in the inability to maintain or restore sufficient functional mass. Therapies are lacking, making transplantation only curative option for end-stage disease. Here, we report on structure-based development characterization (nuclear magnetic resonance [NMR] spectroscopy) first-in-class small molecule inhibitors dual-specificity kinase MKK4 (MKK4i). MKK4i increased upon hepatectomy murine porcine models, allowed survival pigs lethal 85% model, showed antisteatotic antifibrotic effects disease mouse models. A first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with clinical candidate HRX215 was conducted revealed excellent safety pharmacokinetics. trials probe prevention/treatment failure extensive oncological resections grafts warranted.

Язык: Английский

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Hallmarks of cancer resistance

iScience, Год журнала: 2024, Номер 27(6), С. 109979 - 109979

Опубликована: Май 15, 2024

This review explores the hallmarks of cancer resistance, including drug efflux mediated by ATP-binding cassette (ABC) transporters, metabolic reprogramming characterized Warburg effect, and dynamic interplay between cells mitochondria. The role stem (CSCs) in treatment resistance regulatory influence non-coding RNAs, such as long RNAs (lncRNAs), microRNAs (miRNAs), circular (circRNAs), are studied. chapter emphasizes future directions, encompassing advancements immunotherapy, strategies to counter adaptive integration artificial intelligence for predictive modeling, identification biomarkers personalized treatment. comprehensive exploration these provides a foundation innovative therapeutic approaches, aiming navigate complex landscape enhance patient outcomes.

Язык: Английский

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DeepKEGG: a multi-omics data integration framework with biological insights for cancer recurrence prediction and biomarker discovery

Briefings in Bioinformatics, Год журнала: 2024, Номер 25(3)

Опубликована: Март 27, 2024

Abstract Deep learning-based multi-omics data integration methods have the capability to reveal mechanisms of cancer development, discover biomarkers and identify pathogenic targets. However, current ignore potential correlations between samples in integrating data. In addition, providing accurate biological explanations still poses significant challenges due complexity deep learning models. Therefore, there is an urgent need for a method explore provide model interpretability. Herein, we propose novel interpretable (DeepKEGG) recurrence prediction biomarker discovery. DeepKEGG, hierarchical module designed local connections neuron nodes interpretability based on relationship genes/miRNAs pathways. pathway self-attention constructed correlation different generate feature representation enhancing performance model. Lastly, attribution-based importance calculation utilized related interpretation Experimental results demonstrate that DeepKEGG outperforms other state-of-the-art 5-fold cross validation. Furthermore, case studies also indicate serves as effective tool The code available at https://github.com/lanbiolab/DeepKEGG.

Язык: Английский

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Hepatocellular carcinoma: signaling pathways and therapeutic advances

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Фев. 6, 2025

Abstract Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% liver and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) C (HCV), metabolic disorders. There are no obvious symptoms in early stage HCC, which often leads delays diagnosis. Therefore, HCC patients usually present tumors advanced incurable stages. Several signaling pathways dis-regulated cause uncontrolled cell propagation, metastasis, recurrence HCC. Beyond frequently altered therapeutically targeted receptor tyrosine kinase (RTK) involved differentiation, telomere regulation, epigenetic modification stress response also provide therapeutic potential. Investigating key their inhibitors pivotal for achieving advancements management At present, primary approaches (TKI), immune checkpoint (ICI), combination regimens. New trials investigating therapies involving ICIs TKIs or anti-VEGF (endothelial growth factor) therapies, as well combinations two immunotherapy The outcomes these expected revolutionize across all Here, we here comprehensive review cellular pathways, potential, evidence derived from late-stage clinical discuss concepts underlying earlier trials, biomarker identification, development more effective therapeutics

Язык: Английский

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Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

Cells, Год журнала: 2022, Номер 11(4), С. 632 - 632

Опубликована: Фев. 11, 2022

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. It usually diagnosed in an advanced stage characterized by a high intrinsic drug resistance, leading to limited chemotherapeutic efficacy relapse after treatment. There therefore vast need for understanding underlying mechanisms that contribute resistance developing therapeutic strategies would overcome this. The rapid proliferation tumor cells, combination with highly inflammatory microenvironment, causes chronic increase protein synthesis different hepatic cell populations. This leads intensified demand folding, which inevitably accumulation misfolded or unfolded proteins lumen endoplasmic reticulum (ER). process called ER stress triggers response (UPR) order restore or—in case severe prolonged stress—to induce death. Interestingly, three arms signaling pathways have been shown drive chemoresistance several tumors could form promising target. review provides overview how activation UPR contributes HCC.

Язык: Английский

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