Search Results (1,043)

Breast cancer remains one of the most prevalent malignancies worldwide, and radiation therapy is a central component of its management. However, intrinsic or acquired resistance to radiation significantly compromises therapeutic efficacy. This systematic review aimed to identify and evaluate molecular mechanisms and interventions that influence radiation sensitivity in breast cancer models. A comprehensive PubMed search was conducted using the terms “breast cancer” and “radiation resistance” for studies published between 2002 and 2024. Seventy-nine eligible studies were included. The most frequently investigated mechanisms included the dysregulation of the PI3K/AKT/mTOR and MAPK signaling pathways, enhanced DNA damage repair via non-homologous end joining (NHEJ), and the overexpression of cancer stem cell markers such as CD44⁺/CD24⁻/low and ALDH1. Several studies highlighted the role of non-coding RNAs, particularly the lncRNA DUXAP8 and microRNAs such as miR-21, miR-144, miR-33a, and miR-634, in modulating radiation response. Components of the tumor microenvironment, including cancer-associated fibroblasts and immune regulators, also contributed to radiation resistance. By synthesizing current evidence, this review provides a consolidated resource to guide future mechanistic studies and therapeutic development. This review highlights promising molecular targets and emerging strategies to enhance radiosensitivity and offers a foundation for translational research aimed at improving outcomes in radiation-refractory breast cancer. Full article

Metastatic breast cancer (BC) spread underscores the need for novel prognostic biomarkers. This study investigated CCR4-NOT Transcription Complex Subunit 7 (CNOT7) and leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) in BC progression and natural killer (NK) cell resistance. In the current study, 90 female BC patients (46 non-metastatic, 44 metastatic) were analyzed. CNOT7 and LAIR-1 protein levels were measured in serum via ELISA and CNOT7 expression in tissue by immunohistochemistry (IHC). In silico tools explored related pathways. Computational analyses, including in silico bioinformatics and molecular docking, explored gene functions, interactions, and ligand binding to CNOT7 and LAIR-1. CNOT7 serum levels were significantly elevated in metastatic patients (mean 4.710) versus non-metastatic patients (mean 3.229, p < 0.0001). Conversely, LAIR-1 serum levels were significantly lower in metastatic (mean 56.779) versus non-metastatic patients (mean 67.544, p < 0.0001). High CNOT7 was found in 50% (45/90) of cases, correlating with higher tumor grade, hormone receptor negativity, and increased lymph node involvement. Elevated CNOT7 and lower LAIR-1 levels were associated with worse overall survival. Pathway analysis linked CNOT7 to the PI3K/AKT/mTOR pathway. Computational findings elucidated CNOT7′s cellular roles, gene/protein interaction networks for LAIR-1/CNOT7, and distinct ligand binding profiles. High CNOT7 levels are associated with advanced BC stages and poor clinical outcomes, which suggests its utility as a prognostic biomarker. The inverse relationship between CNOT7 and LAIR-1 provides mechanistic insights into BC progression and immune evasion, further supported by in silico investigations. Full article

Despite the successes achieved in recent years in the treatment of childhood acute lymphoblastic leukemia (ALL), high-risk ALL in particular still represents a considerable challenge, with poorer outcomes. The PI3K/AKT/mTOR signaling pathway is frequently constitutively activated in ALL and consequently leads to unrestricted cell proliferation, without showing frequent mutations in the most important representatives of the signaling pathway. Recent studies have shown that fine balanced protein expression is a common way to adjust oncogenic B cell directed receptor signaling and to mediate malignant cell proliferation and survival in leukemic cells. Too low expression of inhibitory phosphatases can lead to constitutive signaling of kinases, which are important for cell proliferation and survival. In contrast, marked high expression levels of key phosphatases enable cells with distinct pronounced oncogenic B cell directed receptor signaling to escape negative selection by attenuating signal strength and thus raising the threshold for deletion checkpoint activation. One of the most important B cell receptor-dependent signaling cascades is the PI3K/AKT signaling pathway, with its important antagonist SHIP1. However, recent data show that the inositol-5-phosphatase SHIP1 is differentially expressed across the heterogeneity of the ALL subtypes, making the overall therapeutic strategy targeting SHIP1 more complex. The aim of this article is therefore to provide an overview of the current knowledge about SHIP1, its expression in the various subtypes of ALL, its regulation, and the molecules that influence its gene and protein expression, to better understand its role in the pathogenesis of leukemia and other human cancers. Full article

The Carbohydrate-Responsive Element-Binding Protein (ChREBP) is a glucose-sensitive transcription factor that regulates the carbohydrate and lipid metabolism. We investigated its cell-type-specific role in hepatocarcinogenesis using a chemically induced mouse model. Additionally, we examined the functions of its isoforms, ChREBPα and ChREBPβ. After the diethylnitrosamine (DEN) administration, we analyzed hepatocellular adenomas and carcinomas in systemic ChREBP-knockout (KO), hepatocyte-specific ChREBP-KO (L-KO), and wildtype (WT) mice at 4, 12, and 36 weeks using histology, morphometry, proliferation measurements, immunohistochemistry, a Western blot, and a quantitative PCR. Tumors developed 36 weeks after the DEN administration in 27% of WT mice but less frequently in KO (18%) and L-KO (9%) mice. However, preneoplastic foci were less common in KO mice but not in L-KO mice (39% vs. 9%; p < 0.05). L-KO hepatocytes exhibited lower proliferation, while KO tumors showed the downregulation of AKT/mTOR signaling, glycolysis, and lipogenesis compared to WT tumors. Our results showed that the liver-specific loss of ChREBPα, while ChREBPβ remained active, significantly reduced the tumor progression, suggesting an oncogenic role for ChREBPα. In contrast, the systemic knockout of both ChREBPα and ChREBPβ reduced the tumor initiation but did slightly prevent tumor progression, indicating that ChREBPβ may exert tumor-suppressive functions. Full article

Cancer is a major threat to human health, and radiotherapy is a key treatment method. However, its effectiveness is often limited by tumor radioresistance. The PI3K/AKT/mTOR signaling pathway is commonly dysregulated in cancers and plays a significant role in radioresistance, though its exact mechanisms remain unclear. This review discusses how this pathway regulates tumor radioresistance and highlights recent progress in the development of related inhibitors in preclinical and clinical studies. These findings aim to guide clinical treatment strategies and provide new approaches to overcoming radioresistance. Full article

Background/objective: Mucosal melanoma (MM) is a poorly responsive, rare and aggressive subtype with few cases having targetable recurrent driver mutations, although Ras/MAPK and PI3K/AKT/mTOR signaling pathway activations are common. Eventual tumor evasion of targeted therapy continues to limit treatment success. Adequate models are necessary to address therapeutic resistance. The relatively greater incidence of naturally occurring MM in dogs, as well as its comparable clinical and pathological characteristics to human MM, represents an opportunity for study as a human MM patient surrogate. Resistance-promoting crosstalk between Ras/MAPK and PI3K/AKT/mTOR signaling under trametinib inhibition of MEK was studied in canine MM. Emphasis was placed on the suppressive effect of trametinib on cell cycle entry and its potential role in drug resistance. Methods: D-type cyclins were investigated following trametinib treatment of five MM cell lines exhibiting differential drug sensitivities. Signaling pathway activation, proliferation, survival, cell death, and cell cycle were analyzed in the context of D-type cyclin expression. Cyclin D2 expression was manipulated using siRNA knockdown or inducible recombinant overexpression. Results: Trametinib diminished cyclin D1 in all cell lines. While relatively trametinib-resistant MM cells exhibited capacity to upregulate cyclin D2, which promoted proliferation, sensitive MM cells lacked similar cyclin D2 compensation. Inhibition of the compensatory cyclin D2 in resistant cells conferred sensitivity. Induced cyclin D2 overexpression in otherwise trametinib-sensitive MM cells promoted survival. Upregulated PI3K/AKT/mTOR signaling under trametinib treatment was suppressed by mTORC1/2 inhibition, which similarly diminished cyclin D2 response. Conclusions: The compensatory switch from preferential reliance on cyclin D1 to D2 plays a role in MM resistance to MEK inhibition. Full article

Lobelia nummularia Lam. is a traditional medicinal herb of which the anticancer mechanisms remain largely unexplored. Here, we demonstrated that its ethanolic extract (LNE) exerts potent anti-breast cancer activity by inducing ROS-dependent mitochondrial apoptosis in MDA-MB-231 cells, a mechanism confirmed via rescue experiments with the antioxidant N-acetylcysteine (NAC). This pro-apoptotic program is driven by a dual mechanism: potent suppression of the pro-survival EGFR/PI3K/AKT signaling pathway and simultaneous activation of the TP53-mediated apoptotic cascade, culminating in the cleavage of executor caspase-3. Phytochemical analysis identified numerous flavonoids, and quantitative HPLC confirmed that key bioactive compounds, including luteolin and apigenin, are substantially present in the extract. These mechanisms translated to significant in vivo efficacy, where LNE administration suppressed primary tumor growth and lung metastasis in a 4T1 orthotopic model in BALB/c mice. Furthermore, a validated molecular docking protocol provided a plausible structural basis for these multi-target interactions. Collectively, this study provides a comprehensive, multi-layered validation of LNE’s therapeutic potential, establishing it as a mechanistically well-defined candidate for natural product-based anticancer drug discovery. Full article

Background/Objectives: The integration of natural compounds in cancer research marked a crucial shift in the modern medical landscape, through a growing acknowledgment of their potential as efficient, less toxic, and cost-effective alternatives to contemporary chemotherapeutics. Liquiritigenin (LIQ) is a compound obtained from different plants, the most important being the Glycyrrhiza species, commonly known as licorice. Methods: This review compiles findings from previously published preclinical studies and experimental research articles focusing on LIQ’s pharmacological effects, with particular attention to its anticancer potential. The relevant literature was identified using established scientific databases and selected based on relevance to cancer biology and LIQ-associated signaling pathways. Results: LIQ demonstrates anti-oxidant, anti-inflammatory, and anti-proliferative effects. It exerts its potential anticancer activities by inducing apoptosis, preventing cell proliferation, and modulating various signaling pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), and so on. Conclusions: LIQ represents a promising natural agent for cancer therapy, with evidence supporting its multifunctional role in targeting tumor growth and survival mechanisms. By providing a detailed analysis of LIQ, this review aims to highlight its therapeutic efficacy across various cancer types and emphasize its importance as a promising compound in cancer research. In addition, this review seeks to bridge the gap between traditional medicine and modern pharmacology and paves the way for LIQ’s clinical application in cancer therapy. Full article

Peripheral artery disease (PAD) is a common vascular disorder in the elderly, often accompanied by frailty syndrome, which is associated with increased inflammation, oxidative stress, and functional decline. Nutritional strategies, particularly those involving bioactive compounds like flavonoids and omega-3 fatty acids, have been suggested as potential approaches to modulate these pathological processes. This narrative review summarizes current evidence regarding the anti-inflammatory and antioxidant effects of flavonoids and omega-3 fatty acids, and their possible roles in mitigating frailty syndrome in patients with PAD. We examine mechanistic pathways including NF-κB, AMPK, PI3K/Akt/mTOR, and Nrf2, which are implicated in chronic inflammation, endothelial dysfunction, and muscle wasting. Although studies in general and aging populations suggest beneficial effects of these compounds on vascular and muscle health, specific evidence in PAD patients remains limited. Flavonoids may reduce pro-inflammatory cytokine production and enhance antioxidant responses, while omega-3 fatty acids have shown potential in modulating inflammatory signaling and supporting vascular repair. Current data provide a basis for further investigation into the dietary modulation of frailty syndrome in PAD. Understanding the impact of these nutrients may offer insights into adjunctive strategies for improving patient outcomes. Full article

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic condition characterized by hepatic lipid deposits, insulin resistance, and inflammation which may progress to non-alcoholic steatohepatitis (NASH) and fibrosis. Protein kinases play an important role in NAFLD development by regulating metabolic and inflammatory pathways. Mitogen-activated protein kinases (MAPKs), protein kinase C (PKC), AMP-activated protein kinase (AMPK), phosphoinositide 3-kinase (PI3K)/AKT, and mechanistic target of rapamycin (mTOR) are all involved in NAFLD and NASH progression. Emerging evidence indicates that Farnesoid X Receptor (FXR) agonists have therapeutic potential by modulating bile acid metabolism, lipid balance, and inflammatory responses. This review examines the mechanistic interplay between FXR agonists and important protein kinases in NAFLD and NASH. FXR agonists activate AMPK, which promotes fatty acid oxidation and reduces hepatic steatosis. They also regulate MAPK signaling, which reduces c-Jun NH2-terminal kinase (JNK)- and p38 MAPK-mediated inflammation. Furthermore, FXR agonists activate the PI3K/AKT pathway, enhancing insulin sensitivity and modulating mTOR signaling to reduce hepatic fibrosis. Clinical studies in NAFLD/NASH indicate that FXR agonists confer metabolic and anti-inflammatory benefits, although optimizing efficacy and minimizing adverse effects remain challenging. Future studies should focus on combination therapies targeting FXR alongside specific kinases to improve therapeutic outcomes. This review highlights the potential of FXR agonists to modulate protein kinase signaling, opening new avenues for targeted NAFLD/NASH therapy. Full article

There have been multiple approved agents for relapsed/refractory (r/r) Diffuse Large B-cell Lymphoma (DLBCL) over the last 8 years. The majority of these therapies act on specific signaling pathways in malignant B-cells. These signaling pathways stem from the B-cell receptor (BCR), Toll-Like Receptor (TLR), PI3K/AKT/mTOR, BCL-2, and XPO-1. In addition, novel therapies that target extracellular proteins (CD19, CD20, CD30, ROR1, and PD-1) have been developed. The purpose of this review is to discuss the various therapies that target these pathways and highlight the success and shortcomings of these novel agents. Full article

Oral cancer, the most common form of head and neck cancer, is worldwide a serious public health problem. Most patients present a locally advanced disease, and face poor prognosis, even with multimodality treatment. They may also develop second primary tumors in the entirety of their upper aerodigestive tract. The most altered signaling pathways are the PI3K/AKT/mTOR, TP53, RB, and the WNT/β-catenin pathways. Genomic and molecular cytogenetic analyses have revealed frequent losses at 3p, 8p, 9p, and 18q, along with gains at 3q, 7p, 8q, and 11q, and several genes frequently affected have been identified, such as TP53, CCND1, CTTN, CDKN2A, EGFR, HRAS, PI3K, ADAM9, MGAM, SIRPB1, and FAT1, among others. Various epigenetic alterations were also found, such as the global hypomethylation and hypermethylation of CDKN2A, APC, MGMT, PTEN, CDH1, TFP12, SOX17, GATA4, ECAD, MGMT, and DAPK. Several microRNAs are upregulated in oral cancer, including miR-21, miR-24, miR-31, miR-184, miR-211, miR-221, and miR-222, while others are downregulated, such as miR-203, miR-100, miR-200, miR-133a, miR-133b, miR-138, and miR-375. The knowledge of this molecular pathogenesis has not yet been translated into clinical practice, apart from the use of cetuximab, an EGFR antibody. Oral tumors are also genetically heterogenous and affect several pathways, which means that, due to the continuous evolution of these genetic alterations, a single biopsy is not sufficient to fully evaluate the most adequate molecular targets when more drugs become available. Liquid biopsies, either resorting to circulating tumor cells, extracellular vesicles or cell-free nucleic acids, have the potential to bypass this problem, and have potential prognostic and staging value. We critically review the current knowledge on the molecular, genetic and epigenetic alterations in oral cancer, as well as the applications and challenges of liquid biopsies in its diagnosis, follow-up, and prognostic stratification. Full article

Autism spectrum disorder (ASD) is a neurodevelopmental condition frequently associated with gastrointestinal symptoms, gut dysbiosis, and metabolic dysfunctions such as insulin resistance (IR). Recent evidence suggests that the gut microbiota may influence both metabolic and neurological processes through the gut–brain–metabolic axis. This review explores the molecular mechanisms linking dysbiosis, IR, and ASD, focusing on pathways such as TLR/NF-κB activation, PI3K/Akt/mTOR disruption, and the action of microbial metabolites, like short-chain fatty acids (SCFAs), lipopolysaccharide (LPS), and γ-aminobutyric acid (GABA). We discuss how dysbiosis may contribute to increased intestinal permeability, systemic inflammation, and neuroimmune activation, ultimately affecting brain development and behavior. Common microbial alterations in ASD and IR—including increased Clostridium, Desulfovibrio, and Alistipes, and reduced Bifidobacterium and butyrate-producing genera—suggest a shared pathophysiology. We also highlight potential therapeutic strategies, such as microbiota modulation, insulin-like growth factor 1 (IGF-1) treatment, and dietary interventions. Understanding these interconnected mechanisms may support the development of microbiota-targeted approaches for individuals with ASD metabolic comorbidities. Full article

Pancreatic cancer cells exhibit a remarkable ability to tolerate nutrient deprivation, a phenomenon termed “austerity,” which enables their survival within the hypovascular tumor microenvironment. Conventional anticancer therapies frequently fail to effectively target these resilient neoplastic cells, posing a significant challenge to the therapeutic management of pancreatic cancer. Consequently, targeting austerity, the ability of cancer cells to tolerate nutrient starvation, represents a promising anti-austerity strategy for developing novel pancreatic cancer therapeutics. In this study, we investigated calliviminone A (CVM-A), a phloroglucinol–meroterpenoid isolated from Callistemon citrinus leaves, for its anti-austerity activity against PANC-1 human pancreatic cancer cells. Calliviminone A exhibited potent preferential cytotoxicity in nutrient-deprived medium (NDM) with a PC₅₀ of 0.57 µM, while showing minimal toxicity in nutrient-rich Dulbecco’s Modified Eagle’s medium (IC₅₀ = 45.2 µM), indicating a favorable therapeutic index. Real-time live-cell imaging revealed that CVM-A induced significant morphological changes, including cell shrinkage and membrane blebbing, leading to cell death within 24 h of NDM. Furthermore, under normal nutrient conditions in Dulbecco’s Modified Eagle’s Medium (DMEM), CVM-A significantly inhibited PANC-1 cell migration (up to 47% reduction at 20 µM) and colony formation (over 80% suppression at 25 µM), suggesting its antimetastatic potential. Western blot studies demonstrated that CVM-A downregulated key survival components of the PI3K/Akt/mTOR signaling pathway, completely inhibiting Akt and p-Akt at 2.5 µM in NDM, and suppressing insulin-induced Akt activation. These findings highlight CVM-A as a promising lead compound for developing novel anticancer therapies that target the adaptive survival mechanisms and metastatic potential of pancreatic cancer in nutrient-deprived microenvironments. Full article

Triple-negative breast cancer is the most aggressive subtype of breast cancer and is associated with the worst prognosis. Conventional chemotherapy remains the gold standard treatment for this disease but is associated with a high relapse rate, highlighting the urgent need for effective targeted therapies. The PI3K/Akt/mTOR pathway, dysregulated in nearly 60% of these cancers, appears to be a prime target. It involves a signaling cascade beginning with PI3K activation followed by activating phosphorylation of Akt and then mTOR complex, which activates oncogenic processes by enhancing protein synthesis, inhibiting apoptosis, dysregulating autophagy and promoting DNA repair that supports tumor cell survival. Moreover, the PI3K/Akt/mTOR pathway plays a central role in the development of chemoresistance. Numerous alterations (activating the mutation of PIK3CA or the loss of tumor suppressor PTEN) may lead to its overactivation. Targeted inhibitors of PI3K, Akt and mTOR have been developed to counteract this dysregulation. However, numerous cancer resistance mechanisms have emerged, reducing their efficacy, for example, reactivation of Akt following mTOR blockade, reactivation of the pathway by insulin signaling or activation of compensatory pathways such as the MAPK pathway, thus limiting their integration into routine practice. To counteract these resistances, combination therapies currently being investigated in clinical trials aim to improve clinical outcomes of PI3K/Akt/mTOR pathway inhibition. The aim of this review was to summarize current therapies developed to target this pathway in TNBC, with a focus on the resistance mechanisms that limit their effectiveness. Full article