Search Results (233)

Background: As a key regulator of centrosome duplication, polo-like kinase 4 (PLK4) is abnormally overexpressed in various tumors and has emerged as an important target for the development of antitumor drugs. Methods: In this study, based on the lead compound ZSL-M001 (PLK4 IC50 = 3.0 μM) previously obtained by our research group, we designed and synthesized 28 novel quinazoline-based PLK4 inhibitors to enhance kinase inhibitory activity using side-chain extension strategies. Results: Among them, compound H24 (PLK4 IC50 < 0.1 nM) exhibited favorable in vitro antiproliferative activity against TRIM37-amplified MCF-7 breast cancer cells (MCF-7 IC50 = 2.37 ± 0.26 μM) and TRIM37-amplified neuroblastoma IMR-32 cells (IMR-32 IC50 = 1.28 ± 0.04 μM). Its activity was superior to that of the positive control LCR-263. Further in vitro biological evaluation demonstrated that H24 inhibited the colony formation of MCF-7 cells in a concentration-dependent manner, induced S/G2-phase cell-cycle arrest, and promoted apoptosis. H24 also showed favorable metabolic stability in human liver microsomes, with a half-life of 61.3 min. However, no obvious TRIM37 amplification-dependent cellular selectivity was observed in TRIM37 non-highly amplified A549 cells or normal human embryonic kidney HEK-293T cells. Given the suboptimal selectivity of the in vitro antiproliferative activity, Aurora kinase A, which shares high homology with PLK4, was selected for further evaluation of its selectivity. The IC50 for Aurora A inhibition was determined to be 151.2 nM, indicating that its broader kinase selectivity remains to be established. Conclusions: In summary, H24 is a highly potent biochemical PLK4 inhibitor and provides a useful lead scaffold for further optimization rather than a fully selective cellular candidate at the current stage. Full article

Cancer is responsible for systemic burdens, most notably cachexia and immunosuppression, that extend far beyond local tumor growth and collectively dictate poor outcomes. While often studied separately, these debilitating syndromes are deeply interconnected. On the basis of emerging evidence of growth differentiation factor 15 (GDF15)’s dual actions in immunity and metabolism, we propose that the stress-responsive hormone GDF15 is hijacked by tumors and repurposed as a central metaboceptive hub that integrates diverse oncogenic stress signals to launch a coordinated, dual pathological cascade. Systemically, it disrupts brain–body communication via glial cell line-derived neurotrophic factor family receptor alpha-like (GFRAL) activation in the brainstem, driving anorexia, metabolic rewiring, and progressive wasting of skeletal muscle and adipose tissue that define cachexia. GDF15 acts as a potent immunosuppressor within the local tumor microenvironment, impairing T cell cytotoxicity and increasing the abundance of regulatory T cells. Crucially, these effects are not parallel but interlinked, forming a self-reinforcing detrimental cycle that accelerates host deterioration and therapeutic failure. This positions the GDF15-GFRAL axis as a unique dual-benefit therapeutic target with the potential to simultaneously ameliorate cachexia, improve patient function and quality of life, and revitalize anti-tumor immunity. Reframing cancer through the lens of a hijacked metabolic sensing system provides an integrated perspective that transforms this formidable challenge of concurrent host wasting and immune evasion into a druggable opportunity, charting a course for novel host-directed therapies that restore systemic homeostasis. Full article

Cancer remains the foremost cause of death globally and presents a major obstacle to increasing life expectancy. The identification of natural anticancer agents is therefore a key research priority. Essential oils (EOs), widely used in traditional medicine, possess diverse biological activities that warrant systematic investigation. Anisosciadium orientale is traditionally regarded as a safe, edible herb; however, its therapeutic potential has not been extensively explored. In this study, the chemical profile of the EO obtained from the aerial parts of A. orientale was characterized using GC–MS analysis. Antioxidant activity was evaluated through hydrogen peroxide and ABTS radical-scavenging assays, whereas anticancer effects and underlying mechanisms were evaluated in multiple cancer cell lines using MTT cytotoxicity assays, flow cytometry, and molecular docking studies. Sixty constituents were identified in the EO, with myristicin and its isomer among the major components. The EO exhibited notable antioxidant and anticancer activities, demonstrating cytotoxicity against lung carcinoma A549 cells with an IC₅₀ of 84.8 µg/mL and inducing significant apoptosis accompanied by G₂/M cell-cycle arrest. Treatment with the EO markedly boosted levels of caspase-3, p53, Bax, and the Bax/Bcl-2 ratio, while downregulating Bcl-2 expression. Molecular docking revealed strong binding affinities of major constituents—particularly myristicin and its isomer—toward the EGFR kinase active site, suggesting a high degree of complementarity with the EGFR kinase domain. Collectively, this study represents the first comprehensive study integrating chemical profiling, in vitro cytotoxicity, mechanistic assays, and molecular docking for A. orientale. These findings position A. orientale EO as a promising scaffold for the development of natural anticancer interventions, providing a foundation for future preclinical exploration. Full article

Background: Esophageal squamous cell carcinoma (ESCC) remains a highly lethal malignancy with limited therapeutic options, in part due to frequent activation of nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2). Gain-of-function mutations in NRF2 disrupt its negative regulation by Kelch-like ECH-associated protein 1 (KEAP1), resulting in sustained NRF2 signaling that promotes tumor growth and resistance to chemotherapy and radiation. We previously identified the FDA-approved drug pyrimethamine (PYR) as an NRF2 inhibitor and demonstrated that inhibition of dihydrofolate reductase (DHFR) represents the primary mechanism underlying its NRF2-suppressive activity, supporting its advancement into a Phase I window-of-opportunity clinical trial (NCT 05678348). Meanwhile, in NRF2^W24C-KYSE70 and NRF2^D77V-KYSE180 cells, PYR promoted NRF2^Mut ubiquitination and proteasomal degradation and shortened its half-life. This study aims to explore additional modes of action by which PYR inhibits NRF2. Methods: Cell cycle analysis was performed by flow cytometry. Cell proliferation, apoptosis and chemosensitivity were assessed by Live-Cell Analysis System, while radiosensitivity was evaluated using X-ray irradiation and the CellTiter-Glo assay. Molecular interactions between NRF2 and KEAP1 were examined through Co-IP and PLA, and the direct binding of PYR to KEAP1 was quantified using ITC and SPR. Molecular docking and dynamic simulations were employed to predict potential PYR-binding pockets within the Kelch domain. Results: Using genetically defined isogenic ESCC cell models, we show that activation of mutant NRF2 (NRF2^Mut) or wild-type NRF2 (NRF2^WT) produces distinct, context-dependent effects on squamous differentiation, proliferation, and therapeutic response. We further demonstrate that PYR restores sensitivity to chemotherapy and ionizing radiation in NRF2^Mut ESCC cells. Mechanistically, short-term PYR treatment promotes KEAP1-dependent proteasome-mediated degradation of NRF2^W24C. Biochemical and biophysical assays indicate that PYR enhances the interaction between KEAP1 and NRF2^W24C in a manner associated with KEAP1-dependent proteasomal degradation. Computational modeling further suggests that PYR may engage a pocket within the Kelch domain to facilitate the NRF2^W24C-KEAP1 interaction. Conclusions: These findings show that PYR functionally restores KEAP1-mediated NRF2 degradation of select NRF2^Mut through a glue-like effect and overcomes therapy resistance in ESCC. Although the proposed glue-like mechanism remains hypothetical, this work supports further investigation into the NRF2–KEAP1 interaction and may inform the development of KEAP1-targeted strategies for NRF2^Mut cancers, including ESCC. Full article

Background/Objectives: Lung cancer (LC) remains the leading cause of cancer-related death worldwide, despite advances in systemic and targeted therapies. A mechanism of survival of tumor cells is metabolic reprogramming, characterized by increased glucose uptake, aerobic glycolysis, and alterations in mitochondrial function. These adaptations seem to support tumor growth, immune evasion, and therapeutic resistance. In parallel, supportive care and specifically nutritional interventions have become essential components of modern oncology. The interplay between metabolic reprogramming and targeted nutritional strategies represents a promising area of investigation that bridges tumor biology with supportive care, aiming to enhance both therapeutic efficacy and patient quality of life. Methods: This narrative review explores the biological and pathophysiological rationale for the ketogenic diet (KD) as a possible complementary intervention in LC management and summarizes the published preclinical and clinical data supporting this rationale. Results: We discuss key aspects of tumor metabolism, including the Warburg effect, glucose dependency, oxidative stress regulation, fatty acid metabolism, lactate cycling and tumor microenvironment interactions, with particular emphasis on how carbohydrate restriction and ketosis may exacerbate mitochondrial dysfunction in cancer cells and modulate inflammatory pathways. Furthermore, we summarize available preclinical and clinical evidence evaluating the KD in oncology and, more specifically, in LC, focusing on feasibility, safety, metabolic effects, and potential synergy with chemotherapy, radiotherapy, and immunotherapy. Conclusions: While preclinical models suggest enhanced treatment efficacy, clinical data remain limited and heterogeneous, with patient adherence representing a major challenge. Further well-designed longitudinal studies are required to clarify the therapeutic role of the ketogenic diet in lung cancer. Full article

Cellular senescence (CSEN) is caused by a variety of factors that trigger complex molecular pathways. These include telomere shortening, oncogene activation and replicative stress, as well as DNA damage caused by genotoxic anticancer drugs and endogenous and exogenous genotoxins. Here, we review the induction of CSEN by exogenous genotoxic insults resulting from food and environmental exposures. The available data show that genotoxins/carcinogens in tobacco smoke and smokeless tobacco, in the environment, in food, beverages and life-style products induce CNS. The exposures include N-nitroso compounds, polycyclic aromatic hydrocarbons, heterocyclic aromatic amines, acrylamide, heavy metals, fine dust, mycotoxins, phytotoxins, and phycotoxins. Also, heme in red meat contributes to CSEN as it catalyzes the formation of genotoxic species in the colon. Induction of CSEN by external genotoxins/carcinogens is bound on the DNA damage response pathway (DDR), which relies on activation of the ATM/ATR-CHK2/CHK1-p53-p21 axis and the p53-independent p16/p14 axis, eliciting cyclin-dependent kinase inhibition and permanent cell cycle arrest. Other factors that can be involved are DREAM, MAPK, cGAS/Sting, and NF-κB. The accumulation of non-repaired DNA damage triggering CSEN following external genotoxic exposures may contribute significantly to the amelioration of senescent cells and organ failure with age in humans. Senescent cells drive, via the senescence-associated secretory phenotype (SASP), inflammation that is involved in many diseases, including cancer. Although most of the studies were performed with in vitro cell systems, the consequences of CSEN induction by genotoxic nutritional components and environmental exposures seem to be underestimated. Since CSEN correlates with aging, it is reasonable to conclude that exogenous genotoxic pollutants contribute significantly to the aging process through CSEN induction. In light of these findings, it is deduced that reducing genotoxin exposures and using “rejuvenation” supplements (senotherapeutics) are reasonable strategies to counteract cellular senescence and the aging process. Full article

Ovarian cancer, the most lethal type of tumour of the female reproductive system, severely threatens women’s life and health. Despite paclitaxel being a key chemotherapeutic agent in the standard treatment for ovarian cancer, the majority of patients eventually develop resistance to paclitaxel, constituting a significant obstacle to successful treatment. KIF26B, a kinesin family protein, is involved in various cancers, but its role in ovarian cancer and chemotherapy resistance is unclear. In this study, we evaluated the role of KIF26B in drug-resistant ovarian cancer and the underlying mechanisms. Bioinformatics analysis revealed that KIF26B was highly expressed in ovarian cancer tissues and was associated with poor clinical characteristics. Moreover, KIF26B expression was consistently high in chemotherapy-resistant tissues across multiple treatment subgroups, with ROC curve analyses confirming its predictive power for chemoresistance, particularly in advanced serous ovarian cancer. To further investigate the role of KIF26B in ovarian cancer resistance, the effects of KIF26B on cell proliferation, colony formation, the cell cycle, apoptosis, and microtubule polymerization under paclitaxel treatment were assessed. KIF26B knockdown significantly reduced paclitaxel resistance in ovarian cancer cells, inhibited cell proliferation, and promoted apoptosis. Furthermore, KIF26B interference induced cell cycle arrest and altered microtubule polymerization dynamics in paclitaxel-resistant cells. Additionally, our analyses revealed a negative correlation between KIF26B and SLC7A11 in ovarian cancer, particularly in chemoresistant tissues. Combined KIF26B and SLC7A11 expression provided stronger prognostic value than either gene alone did, and functional assays demonstrated that SLC7A11 contributed to the regulation of the KIF26B-mediated paclitaxel response. Overall, our results indicate that KIF26B is crucial for ovarian cancer progression and chemotherapy resistance, likely through SLC7A11 regulation. KIF26B may serve as a potential therapeutic target for overcoming paclitaxel resistance. Full article

Mushrooms are valued for their nutritional qualities and have been used in traditional medicine since the Neolithic era. They exhibit various bioactivities, including antioxidant, hypocholesterolemic, immunomodulatory, and anticancer effects. The anticancer effects arise via direct action on tumor cells and indirect modulation of the immune system; the latter is the predominant mechanism. Numerous studies indicate that various mushroom species are potent immunostimulants because their cell wall polysaccharides and proteoglycans are recognized by intestinal immune cells. This enhances antitumor immunity through multiple molecular pathways. However, their direct effects on cancer cells are of questionable physiological relevance due to bioavailability constraints. Nevertheless, we hypothesize that the accumulation of non-absorbed polysaccharides in the gastrointestinal tract positions mushrooms as dual-action agents with the potential to treat colorectal cancer by providing indirect immunomodulation and direct local tumor suppression. Conversely, the direct anticancer effects of mushrooms are generally attributed to bioactive secondary metabolites that influence essential cellular processes, including signaling pathways, cell cycle regulation, apoptosis, autophagy, cellular migration, invasion, and cancer stem cell characteristics. Beyond these anticancer effects, clinical evidence suggests that certain mushroom-derived substances can improve survival outcomes for cancer patients and provide supportive care benefits in oncology, thereby improving quality of life. Specifically, mushrooms may mitigate the side effects of chemotherapy and radiotherapy, bolster immune function often suppressed by cancer treatments, and enhance overall well-being. In this review, we discuss the therapeutic benefits of dietary and medicinal mushrooms in cancer care, as well as unresolved challenges and future research directions. Full article

Colorectal cancer (CRC) is a life-threatening malignancy, but our understanding of its pathogenic mechanisms remains incomplete—posing a major constraint on the development of effective therapeutic strategies. The transcription-translation feedback loop of clock genes (e.g., BMAL1, CLOCK, PER1/2/3, and CRY1/2) provides a promising novel avenue for deciphering the initiation and progression of CRC. Mounting evidence indicates that core circadian clock genes play pivotal roles in CRC oncogenesis by orchestrating the regulation of the cell cycle, epithelial–mesenchymal transition (EMT), metabolic reprogramming, and the tumor microenvironment. This review systematically summarizes the expression patterns and mechanistic roles of core clock genes in CRC, while elucidating their molecular underpinnings in tumor progression via key signaling cascades (e.g., Wnt/β-catenin and c-Myc/p21 pathways). We emphasize the associations between circadian disruption and CRC—including diagnostic markers, prognostic assessment, and chemosensitivity—and provide an in-depth discussion of chronotherapeutic strategies and their translational potential. Finally, we identify unaddressed scientific questions and propose future research directions to facilitate the development of novel targeted therapies for CRC. Full article

Background/Objectives: Recent preclinical studies suggest that acute exercise induces immune modulation, enhances tumor blood perfusion, and is associated with reduced tumor growth. Adding exercise to immunochemotherapy treatment (ICT) has been proposed as a strategy to increase treatment effectiveness. The ERICA trial (NCT04676009) aimed to assess the feasibility of acute aerobic exercise performed immediately before the administration of ICT in patients with metastatic non-small cell lung cancer (mNSCLC) and to explore hypothesis-generating outcomes related to physical fitness and patient-reported outcomes. Methods: Newly diagnosed mNSCLC patients were randomly assigned (2:1) to the exercise or control group. The exercise intervention included supervised acute exercise before each of four ICT cycles plus a 3-month home-based walking program with an activity tracker and step goals. The feasibility of the exercise protocol was assessed through adherence, acceptability, tolerability, and safety. Clinical, physical, and patient-reported outcomes were assessed at baseline and after 3 months. Results: Twenty-six patients (mean age 60.6 years; SD 10.65) participated, with an 87.5% acceptance rate. In the exercise group (n = 17), 80.9% of participants completed the acute exercise sessions, with a median interval of 38 min [IQR, 20–60] between exercise and ICT. No exercise-related adverse effects were reported. After 3 months, 60% of participants in the exercise group were classified as active and maintained their step goals. Self-reported measures suggest that maintaining physical fitness is favorable for reducing fatigue and insomnia, and therefore improving quality of life. Conclusions: Acute exercise performed immediately before each ICT administration in patients with mNSCLC appears feasible and safe. Full article

Background: Genomic integrity is crucial to the cellular life cycle, which involves a tightly regulated process where cells progress through specific phases to ensure that fully replicated, undamaged DNA is inherited by daughter cells. Any dysfunction in this process or unrepaired DNA damage leads to cell cycle arrest and programmed cell death. Cancer cells are known to exploit these mechanisms to continue dividing. Usually, DNA damage arrests replication, allowing the DNA Damage Response (DDR) pathway to activate, which repairs the DNA or bypasses the damage to support cell survival and preserve genome integrity. For DNA damage bypass or translesion synthesis (TLS), a group of low-fidelity polymerases perform error-prone DNA synthesis opposite damaged bases, where REV1 functions as the main scaffolding protein. Previously, we reported non-TLS functions of REV1, including its role in triggering DNA damage-dependent specific DNA metabolic processes. Methods and Results: In this study, we demonstrate that REV1 plays a significant role in cell cycle progression and that its loss causes arrest at the G2/M phase in flow cytometry analysis. This unexpected phenotype includes dysregulation of G2/M regulators, such as Cyclin B1 and tubulins, in REV1-deficient cells compared to controls, as quantified by Western blot. Additionally, phosphorylation of histone H3 at serine 28 was significantly reduced in these REV1-deficient cells. These G2/M arrest features were even more pronounced in REV1-deficient cells treated with the tubulin inhibitor colchicine. Conclusions: Overall, this study reveals a previously unrecognized link between REV1 TLS polymerase inhibition and the G2/M cell cycle arrest. Full article

Background/Objectives: Colon cancer is the third most common type of cancer in the world, characterized by a high risk of metastasis, resistance to various drugs, and late diagnosis. In addition, the drugs used for treatment are associated with serious neurological damage, causing acute and chronic pain and compromising the patient’s quality of life. Meanwhile, lectins are proteins capable of exerting cytotoxic action on cells from various tumors in a selective manner, without exerting significant toxicity on healthy cells. Despite this, studies on the potential of lectins obtained from microalgae are still scarce in the literature. In this sense, the objective of this study was to evaluate the antitumor activity of lectin isolated from the microalgae Chlorella vulgaris (CvL) on colorectal cancer cells, HT-29. Methods: The purified lectin was tested for cytotoxicity using MTT colorimetric methods, in addition to clonogenicity, cell cycle, apoptosis, and necrosis tests, analyzed by flow cytometry. Results: The assays demonstrated that the lectin was able to induce cell death in the HT-29 tumor line by approximately 83.75% with an IC₅₀ value of 21.5 µg/mL⁻¹, reduced colony formation by more than 90%, was able to regulate the cell cycle by apoptosis, and did not present significant necrosis. These results show that microalgae lectins have the potential to be exploited in the control of neoplastic cells. Full article

Prostate cancer (PCa) is the second most prevalent cancer among men and a major cause of cancer-related mortality worldwide. Despite an initial favorable response to hormone-based therapies, many patients ultimately develop an advanced and lethal form of the disease, referred to as castration-resistant PCa (CRPC). CRPC is associated with poor prognosis and a lack of effective curative treatments. As a result, new alternatives or improved therapeutic strategies to combat this life-threatening condition are urgently needed. Chalcones, also referred to as 1,3-diphenyl-2-propen-1-ones, have attracted significant attention because of their potent antitumor properties. Owing to their distinctive chemical structure and diverse biological activities, these compounds are promising candidates for treating various cancers, including PCa. Both naturally occurring and synthetically derived chalcones have demonstrated anticancer potential by modulating key cellular processes, including apoptosis, cell cycle regulation, cell migration, invasion, metastasis and angiogenesis, as well as major signaling pathways, such as PI3K/Akt/mTOR, androgen signaling, and NF-κB. This review aims to outline the recent advances in the therapeutic potential of chalcone derivatives in prostate cancer, with a focus on their molecular targets, mechanisms of action, and translational relevance. Full article

Background/Objectives: Breast cancer remains one of the most prevalent and life-threatening malignancies worldwide. This study describes the design and biological evaluation of a series of secosteroid–2-pyrazoline hybrids as novel antitumor agents against ERα-positive breast cancer cell lines MCF-7 and T47D. Methods: A simple and efficient method for synthesizing secosteroid–2-pyrazoline hybrids was developed starting from 13α-hydroxy-3-methoxy-13,17-secoestra-1,3,5(10)-triene-17-oic acid hydrazide and 1,3-diketones. The resulting secosteroid derivatives were evaluated against hormone-dependent MCF-7 and T47D breast cancer cells. Furthermore, the selectivity and effects of three lead compounds on signaling pathways in MCF-7 cells were examined. Flow cytometry was used to assess the cell-cycle distribution of MCF-7 cells treated with the lead compound. Results: Among the synthesized hybrids, compounds 3f, 3j, and 3k exhibited potent antiproliferative activity with IC₅₀ values of 0.2–0.5 μM against breast cancer cells, while demonstrating very low cytotoxicity towards normal cells (IC₅₀ > 25 μM), indicating a favorable safety profile. The antitumor activity of lead compound 3j was additionally investigated in combination with standard chemotherapeutics, docetaxel and doxorubicin, yielding synergistic effects. The lead compounds showed a dual mechanism of action by inhibiting S6 kinase and promoting Bcl-2 phosphorylation at 0.9 μM, without significantly affecting hormonal breast cancer targets such as ERα, GREB1, and AR. Compound 3j induced apoptosis accompanied by a reduction of the G1/G0 phase in MCF-7 cells. Conclusions: These findings highlight secosteroid–2-pyrazoline hybrids as promising candidates for the development of next-generation breast cancer therapeutics targeting apoptosis and S6K signaling pathways. Full article

Cellular senescence is an irreversible cell cycle arrest, triggered by stressors like telomere shortening, DNA damage, and oncogenic signaling. These cells, often referred to as ‘zombie cells’ because they cease dividing yet resist apoptosis, drive the Senescence-Associated Secretory Phenotype (SASP), releasing pro-inflammatory cytokines, chemokines, growth factors, and matrix-remodeling enzymes. While senescence is a protective mechanism against malignant proliferation, its persistence in tissues contributes to aging and age-related diseases (inflammaging). Recognizing this dual role forms the basis for developing therapies that bridge anti-aging, regenerative medicine, and oncology, as precise molecular regulatory mechanisms remain incompletely understood. This review interrelates these disciplines, focusing on targeted interventions against senescent cells (SnCs). These interventions include senolytics (agents that selectively eliminate SnCs) and senomorphics (agents that suppress the SASP), offering translational insights from anti-aging/aesthetic applications into integrated treatment models. The framework addresses cancer therapeutics via immunologic modalities such as monoclonal antibodies (mAbs) and CAR T-cell therapy, alongside nucleic acid-based therapeutics (mRNA and siRNA), and is used in combination with broad-spectrum therapeutics. The novelty lies in synthesizing these disparate fields, unified by cellular senescence as a central mechanistic target. Ultimately, the goal is to identify targets that induce tumor regression, mitigate age-related vulnerabilities, promote tissue homeostasis and regeneration, and improve quality of life and overall survival. Full article