Search Results (5,535)

Cancer ranks as one of the top causes of death worldwide, and the World Health Organisation (WHO) estimates an increase of up to 55% in cases over the next 15 years, reaching 300 million cases worldwide. Current approaches to the treatment of cancer, such as chemotherapy and radiation therapy, have been used with continuous significant advancements. However, these conventional methods have harmful side effects that can last a lifetime. Today, there is growing interest in developing alternative cancer therapies from natural products or complementary medicine. One of the natural sources that has shown promise as an anticancer agent is honey, which has long been applied as a complementary medicine, and its beneficial health effects on various diseases in both animal and human models have been widely studied. Malaysian honey, such as Tualang, pineapple, Gelam, Kelulut, and Acacia, possesses a rich composition of phytochemicals, including polyphenols and flavonoids, which are reported to have promising anticancer properties. Examples of the phytochemicals highlighted in this review are phenolic acid, syringic acid, salicylic acid, p-coumaric acid, gallic acid, benzoic acid, caffeic acid, chrysin and its derivatives, kaempferol, fisetin, catechin, apigenin, quercetin, acacetin, pinocembrin, pinobanksin, hesperetin, naringenin, vitexin, isoorientin, xanthohumol, and galangin. This review highlights the anticancer mechanisms and molecular pathways of the phytochemicals found in Malaysian honey, focusing on their antioxidant effects, induction of mitochondrial-mediated apoptosis, inhibition of angiogenesis and metastasis, and suppression of cancer cell proliferation. The findings of various studies published in the past five years are collated to understand their mechanisms of action. Full article

Background: Breast cancer brain metastases (BCBM) lack effective treatments, contributing to breast cancer-related morbidity and mortality. Integrating translational animal models and advanced non-invasive imaging can accelerate the development of urgently needed therapies. Method: In this study, we developed an intracarotid method mimicking BCBM and compared it to the stereotactic model in terms of animal welfare, tumour establishment, and blood–brain barrier (BBB) permeability. BCBM was established through intracarotid or stereotactic inoculation of BT474 and MDA-MB-231.Luc2 cells in NMRI nude mice. We utilised magnetic resonance imaging (MRI) and bioluminescence imaging (BLI) to monitor tumour growth and BBB permeability, supported by fluorescent immunohistochemistry for validation. Finally, light sheet microscopy (LSM) was employed to visualise tumour establishment in intact brains. Results: Both inoculation methods achieved a survival rate >70%, with animals recovering within a week post-surgery. MRI and BLI effectively visualised tumour growth with stereotactic implantation, resulting in single tumours, while intracarotid inoculation led to micro-seeding of up to seven tumours in one brain. Tumour growth was rapid and homogenous in the stereotactic model, whereas the intracarotid model exhibited slower, heterogenous growth. Notably, BBB permeability was significantly higher in small tumours in the stereotactic model when compared to the intracarotid model (p = 0.003). Ex vivo analyses validated these findings with the identification of multiple metastasis in the intracarotid model and single tumours in the stereotactic model. Conclusion: We developed an animal model that closely mimics BCBM, highlighting extravasation and micro-seeding while maintaining animal welfare. Our established imaging protocols enable longitudinal evaluations of BBB permeability and treatment response, creating a translational platform for testing novel anti-cancer therapies. Full article

Temozolomide and dacarbazine are untargeted anticancer prodrugs that have been widely employed in the treatment of melanoma and glioblastoma. These agents decompose into a short-lived monomethyl triazene intermediate, culminating in the release of a methyl diazonium cation that serves as the DNA-alkylating species responsible for tumour destruction. However, due to their high chemical lability, these agents have been associated with chemotherapy resistance, mutagenicity, tumour relapse, and significant off-target toxicity. One promising strategy towards the resolution of these limitations involves the design of arylmethyl triazene prodrugs, which enable targeted tumour-specific drug delivery. This review explores the various approaches used to selectively deliver alkyl aryl triazenes as alternatives to current therapies. It highlights early chemical strategies such as N-acylation and etherification of monomethyl triazenes, along with associated kinetic studies. The selective activation of novel triazenes in murine and human melanoma cells through a tyrosinase-responsive promoiety is discussed. Recent progress in nitroaromatic-based prodrugs designed to exploit the hypoxic microenvironment of glioblastoma is also examined. Additionally, we summarise the development of combi-triazenes and their underlying chemistries, which enable the simultaneous release of two active therapeutic agents. Full article

The remarkable evolution of oncological therapies has dramatically improved cancer survival rates but has simultaneously introduced a significant burden of cardiovascular complications. Cardio-oncology has emerged as a critical multidisciplinary field focused on mitigating the “collateral damage” of life-saving anticancer treatments, ranging from traditional chemotherapeutics to novel immunotherapies. This review provides a comprehensive analysis of the pathophysiological mechanisms, clinical phenotypes, and evolving management strategies for cancer therapy-related cardiac dysfunction (CTRCD). An extensive synthesis of the current literature was conducted, focusing on the molecular pathways of cardiotoxicity, including Topoisomerase IIβ inhibition by anthracyclines, HER2 signaling disruption by targeted agents, and immune-mediated myocarditis triggered by checkpoint inhibitors (ICIs). Cardiotoxicity is increasingly recognized as a spectrum of phenotypes. Heart failure with reduced ejection fraction (HFrEF) remains a primary concern with cytotoxic agents, while heart failure with preserved ejection fraction (HFpEF) is emerging as a critical complication of radiation therapy and tyrosine kinase inhibitors (TKIs). The integration of advanced diagnostic tools—specifically Global Longitudinal Strain (GLS) and Cardiac Magnetic Resonance (CMR) mapping—has shifted the clinical focus toward subclinical detection. Furthermore, pivotal clinical trials such as PRADA and SUCCOUR have validated early pharmacological prophylaxis and strain-guided interventions. Emerging challenges, including the management of CAR-T cell-induced cytokine release syndrome and the specific cardiovascular needs of pediatric and geriatric populations, are also explored. The future of cardio-oncology lies in precision medicine, leveraging genomic profiling and artificial intelligence to identify high-risk individuals. A proactive, multidisciplinary approach is essential to ensure that the success of modern oncology is not compromised by irreversible cardiovascular morbidity. Full article

Bladder cancer (BCa) is the second most common cancer of the genitourinary tract globally. It has limited treatment options, high recurrence rate, and acquires resistance to platinum-based therapy. Therefore, identifying novel therapeutic targets is urgently needed. Analysis of the TCGA data revealed that the enzyme galactokinase-1 (GALK1) is overexpressed (p < 0.0001) in bladder tumors compared to normal tissue. Our data also confirmed GALK1 protein upregulation in multiple human BCa cell lines and rodent bladder tumors. However, the precise role of GALK1 in BCa progression and effects of its specific inhibitor remain unexamined. In this study, we demonstrate that GALK1 gene silencing using shRNA resulted in a significant reduction in BCa cell proliferation, migration, and invasion. Pharmacological inhibition of GALK1 using small molecule Cpd36 resulted in anticancer efficacy against BCa. Cpd36 inhibited proliferation, migration, and invasion of BCa cells. Further, Cpd36 induced G1 phase cell cycle arrest, apoptosis, mitochondrial membrane depolarization, and ROS production in the BCa cells. Mechanistically, Cpd36-induced reduction in cell proliferation was associated with a decrease in expression of GALK1, PCNA proteins. Inhibition of metastatic potential was accompanied by decreased migration, invasion, and MMP-9 expression. Cell cycle arrest was associated with decrease in Cyclin D1 and increased expression of p21 and p27. Induction of apoptosis was linked with increased expression of cleaved caspase-3 and cleaved PARP, while downregulating p-AKT. Additionally, Cpd36 in combination with cisplatin or gemcitabine showed a strong synergistic effect on BCa cells. Taken together, our findings suggest that GALK1 plays a significant role in BCa cell survival and validates its inhibitors as promising therapeutic options for managing this disease. Full article

Breast cancer is the most commonly diagnosed cancer among women, with approximately one in eight women developing the disease during their lifetime. Despite advancements in current treatment options, breast cancer was responsible for an estimated 670,000 deaths worldwide in 2022. This highlights the urgent need for the development of novel therapeutic strategies. Historically, plant-derived compounds have played a significant role in cancer therapy, exemplified by widely used chemotherapeutic agents such as paclitaxel and docetaxel. In recent years, increasing attention has been directed toward novel plant-derived compounds as potential anti-cancer agents. Among these, Naringenin, a flavonoid predominantly found in citrus fruits, has shown promising antioxidant, anti-inflammatory, and anti-cancer properties. This review highlights recent studies investigating the effects of Naringenin and its derivatives on breast cancer. Evidence from both in vitro and in vivo animal models suggests that Naringenin may exert anti-tumor activity by inhibiting cell proliferation, promoting apoptosis, modulating key cell signaling pathways, and enhancing radio-sensitivity in breast cancer cells. Although preclinical evidence strongly supports the anticancer potential of Naringenin in breast cancer, comprehensive clinical studies are urgently needed to validate its efficacy and safety in humans. Full article

Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality in the world. Although there is an armamentarium of therapeutic options available for HCC therapy, current treatment modalities still face challenges, such as limited effectiveness and resistance to therapy due to inherent intratumoral heterogeneity. Hence, the development of novel therapeutics is an unmet need. Microalgae possess the ability to provide naturally derived compounds that are attractive for biomedical applications. The multifunctional nature of microalgae, with its unique combination of anticancer metabolites, oxygen-generating capability, and photosensitizing activity, make them a versatile platform for developing next-generation cancer therapeutics. In light of the above, this succinct narrative review highlights the potential biomedical applications of microalgae in cancer therapy, with a focus on HCC. Preclinical studies have shown the significant potential of microalgae as naturally occurring sources of chemopreventive and anticancer agents against HCC. Future directions include the use of biotechnology to enhance the production of microalgal-derived bioactive compounds and the formulation of biocompatible and biodegradable drug–microalgae embolic agents with prolonged release of anticancer drugs, thereby giving rise to synergistic antitumor effects, and their application for the delivery of immune checkpoint inhibitors for immunotherapy in HCC. Overall, microalgae hold considerable promise for advancing innovative therapeutic strategies against HCC. Full article

Glioblastoma is the most aggressive primary malignant tumor of the central nervous system in adults, with a poor prognosis and high resistance to conventional therapies. Platinum drugs like cisplatin are effective but limited by systemic toxicity, poor blood–brain barrier penetration, and resistance. Natural compounds are increasingly studied for their anticancer potential and ability to enhance existing therapies. Based on this rationale, we designed Pt(IV)Ac-GA, a novel platinum(IV) complex obtained by conjugating cisplatin with ganoderic acid A, a triterpenoid from Ganoderma lucidum known for anticancer and immunomodulatory effects. The compound was synthesized, structurally characterized, and showed high stability and favorable pharmacokinetics. In vitro, Pt(IV)Ac-GA strongly reduced the viability of U251 and T98G glioblastoma cells while sparing normal astrocytes. It triggered apoptosis, cell cycle arrest, impaired migration, and increased sensitivity to ferroptosis and mitochondrial dysfunction. These results highlight Pt(IV)Ac-GA as a promising candidate to overcome current limitations in glioblastoma treatment. Full article

Hepatocellular carcinoma (HCC) is a highly malignant tumour with a poor prognosis and few effective treatment options. Development of resistance to conventional therapies and occurrence of severe side effects highlight the urgent need for novel, low-toxicity interventions. Natural products are promising candidates for HCC drug development thanks to their multi-target activity and favourable safety profiles. Previous studies reported that Lingonberry extract, a bioactive natural product, inhibits proliferation of HepG₂ cells. However, the key molecular targets and underlying anticancer mechanisms remain unclear. In this study, we analysed gene chip data from Lingonberry extract-treated HepG₂ tumour-bearing mice using bioinformatics tools, employing a cross-species, multi-level screening strategy to identify PSMB8 as the core regulatory gene. In vitro functional validations (Western blotting, RT-PCR, CCK-8 assay, colony formation assay, flow cytometry and TUNEL staining) confirmed these findings. Downregulating PSMB8 was found to effectively induce late apoptosis in HepG₂ cells, and Lingonberry extract was found to significantly reduce PSMB8 protein expression. This study identifies PSMB8 as a key mediator of the anticancer effect of Lingonberry extract in HepG₂ cells. It provides a reliable methodological reference for screening anticancer targets of natural products and supports further exploration of Lingonberry extract as a potential adjuvant/lead compound for HCC. Full article

Introduction: Osteosarcoma (OS) is the most common primary malignant bone tumor in children and young adults, with poor prognosis due to relapse, metastasis, and chemoresistance. The search for novel metal-based therapeutics has highlighted copper complexes as promising candidates. Here, we report the in vitro and in vivo antitumor activity of a tetranuclear Cu(II)-hydrazone complex (Cu₄L₄) derived from (E)-5-chloro-N′-(2-hydroxy-3-methoxybenzylidene)thiophene-2-carbohydrazide. Results: Cytotoxic assays on MG-63 OS cells revealed potent activity with an IC₅₀ of 0.50 ± 0.04 µM, significantly surpassing its free ligand (IC₅₀ = 13.9 ± 1.6 µM) and cisplatin (IC₅₀ = 39.0 ± 1.8 µM). This tetranuclear complex outperforms mononuclear Cu-hydrazones analogs (e.g., 4-fold vs. CuHL1, 2-fold vs. CuHL2, 5-fold vs. CuHL3, 17-fold vs. CuHL4,), and Cu₄L₄ also exhibits reduced clonogenic survival, induces reactive oxygen species production, and promotes late apoptosis as a main mechanism, being the main mechanism of action involved in anticancer activity. In multicellular tumor spheroids, the complex maintained strong cytotoxicity (IC₅₀ = 4.11 ± 0.12 µM), impaired spheroid integrity, and markedly inhibited cell migration at sub-IC₅₀ concentrations. The tetranuclear architecture confers markedly enhanced antitumor activity relative to the corresponding mononuclear Cu–hydrazone complexes (e.g., 2-fold vs. CuHL1, 4-fold vs. CuHL2, 2-fold vs. CuHL3). In a xenograft model, sustained administration of Cu₄L₄ (2 mg/kg, i.p., twice weekly) inhibited tumor growth by 43.6%, reduced mitotic index, and increased necrotic area without significant systemic toxicity. Conclusions: Overall, Cu₄L₄ displayed potent and selective antitumor activity against OS cells in 2D, 3D, and in vivo models, underscoring copper–hydrazone complexes as promising scaffolds for the development of new therapies against OS. Full article

Triple-negative breast cancer (TNBC) remains one of the most aggressive breast cancer subtypes and is associated with limited therapeutic options, underscoring the urgent need for novel treatment strategies. In this study, a library of seventeen 1,3,5-triazine derivatives potentially targeting TNBC was developed using an activity-based approach. Compounds were synthesized via an ultrasound-assisted protocol, providing an efficient and environmentally friendly methodology. The synthesized library was evaluated in vitro against the human TNBC cell lines MDA-MB-468, MDA-MB-231, and Hs578T, as well as the non-tumorigenic epithelial cell line MCF10A. Compounds 9 and 17 exhibited the most promising antiproliferative activity against TNBC cell lines (MDA-MB-468: IC₅₀ = 36.62 µM for 9 and 38.29 µM for 17; MDA-MB-231: IC₅₀ = 37.32 µM for 9 and 32.86 µM for 17; Hs578T: IC₅₀ = 57.26 µM for 9 and 34.87 µM for 17), while maintaining acceptable selectivity toward non-cancerous cells. The lead compounds were further assessed in vivo using a Danio rerio model to evaluate general toxicity and cardiotoxicity. In addition, ADME parameters were predicted for all compounds using biomimetic chromatography. Overall, compounds 9 and 17 emerged as promising small-molecule candidates for TNBC treatment, requiring further toxicological evaluation in more human-relevant in vivo models. Full article

The technological promise of nonlinear optical (NLO) compounds has stimulated intense interest in optoelectronic devices, data storage, photonics, and anticancer therapy. Thiosemicarbazone ruthenium materials are of growing interest because of their tunable ligand framework and coordination sphere, allowing fine control over geometry, electronics, and functional properties. Here, we report an N-substituted salicylaldehyde thiosemicarbazone ligand and a series of octahedral Ru(III) complexes bearing triphenylphosphine or triphenylarsine and halide (Cl, Br) co-ligands. The complexes were characterized by elemental analysis, FT-IR, UV–Vis, EPR, mass spectrometry, and magnetic susceptibility measurements, which together confirm NS-chelation to a low-spin Ru(III) center in a distorted octahedral environment. Their photophysical and NLO responses were assessed by UV–Vis spectroscopy and powder second-harmonic generation measurements (Kurtz–Perry method), revealing promising NLO behavior. In parallel, antioxidant activity and in vitro anticancer effects against HeLa cells were evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assays. These results provide insight into ligand-controlled structure–activity relationships, in which the halide (Cl/Br) and ancillary triarylphosphine co-ligands regulate electronic interactions and lipophilicity and ultimately increase biological performance, underscoring the dual materials and medicinal potential of these Ru(III) complexes. Full article

Colorectal cancer (CRC) is still a leading cause of cancer-related death worldwide, and often, conventional chemotherapeutics exhibit limited efficacy. The hydroalcoholic leaf extract of Cynara cardunculus subsp. cardunculus (wild artichoke) was investigated for its anticancer potential in CRC and effects on enteric pathogens. Nine phenolic compounds were identified by high-performance liquid chromatography with diode-array detection (HPLC-DAD), and spectrophotometric analyses were applied for total phenolic (TPC: 178.33 mg GAE/g) and total flavonoid (TFC: 52.21 mg CE/g) content quantification. The extract exhibited good antioxidant activity on DPPH (IC₅₀: 21.35 μg/mL), ^−•O₂ (IC₅₀: 1.56 μg/mL), and H₂O₂ (IC₅₀: 314.73 μg/mL) and was found to inhibit the growth of pathogenic enteric bacteria, with Enterococcus faecalis and Staphylococcus aureus being the most sensitive. In CaCo-2 CRC cells, the extract induced a concentration-dependent cytotoxicity (IC₅₀: 13.07 μg/mL at 24 h) through increased production of reactive oxygen species (ROS), upregulation of Nrf2, and induction of apoptosis, as evidenced by elevated p53, Bax, cytochrome c, and caspase-3 levels. No necrosis, measured by lactate dehydrogenase (LDH) release, or toxicity to HFF-1 normal fibroblasts was observed at concentrations up to 50 μg/mL. Additionally, CCE demonstrated synergistic effects with 5-FU (combination index < 0.8). This evidence suggests that CCE exhibits selective antitumor activity and chemosensitizing properties, supporting its possible development as an adjunctive agent in CRC therapy. Full article

Ferroptosis is a recently discovered form of cell death, driven by membrane lipid peroxidation with the contribution of intracellular iron. In recent years, many researchers have discovered the involvement of ferroptotic mechanisms in the etiology of various diseases, including several forms of cancer. Different points in the ferroptotic pathway can be crucial for arising or sustained pathologies, given the contribution of numerous molecular mechanisms concerning membrane channels, several proteins, enzymes, and also kinases. The latter, in particular, seem to be very important in the control of ferroptosis in different manners depending on the pathology. Therefore, many articles in recent years have described how the pathways that involve kinases can determine, control, or alter the physiological ferroptotic contribution. Interestingly, in a tumoral context, oncogenes and tumor suppressor activity affect the correct ferroptotic process directly or indirectly promoted by abnormal kinase activity. Expanding the understanding of how kinases contribute to tumorigenesis by altering ferroptosis mechanisms may provide important insights to improve current anticancer therapies. Furthermore, new data have indicated how kinase-dependent ferroptotic activity may influence the efficacy of immunotherapy. Since one of the major obstacles to this promising anticancer therapy concerns the resistance induced by cancer cells, finding new targets, such as kinases, to improve ferroptosis in tumor cells could open an intriguing door to enhancing immunotherapy and overcoming the current obstacle. Full article

CRISPR screens are a powerful functional genomics approach for identifying genes that confer sensitivity and resistance to anti-cancer therapies. CFI-402257 (luvixasertib, 2257) is a small molecule inhibitor of threonine tyrosine kinase (TTK), a promising therapeutic target in genomically unstable cancers due to its critical role in establishing the spindle assembly checkpoint (SAC) during mitosis. To inform its ongoing development and evaluation in clinical trials, we sought to use CRISPR activation (i.e., gain of function) screens to identify cellular mechanisms of resistance to 2257 in models of triple-negative breast cancer (TNBC). In vitro screens conducted in two TNBC cell lines nominated ABCG2 as the top resistance-conferring gene in both models. Validation studies assessing clonogenic survival and apoptosis confirmed that ABCG2 overexpression enhanced TNBC resistance to 2257 in vitro, while knockdown enhanced sensitivity. These findings suggest that 2257 is a substrate of ABCG2’s drug efflux activity. However, overexpression of ABCG2 failed to confer resistance to 2257 in TNBC xenografts grown in mice and treated with a moderately active dose and schedule. Our results highlight the potential impact of drug transporters in in vitro CRISPR screens and the importance of confirming the relevance of drug response mechanisms identified in cultured cells using in vivo models that recapitulate drug pharmacokinetics and pharmacodynamics. Full article