Salinomycin (SAL), originally identified for its potent antibacterial properties, has recently garnered attention for its remarkable activity against a variety of cancer types. Beyond its direct cytotoxic effects on cancer cells, SAL can also enhance the efficacy of anti-CD20 immunotherapy in B-cell malignancies, both in vitro and in vivo. Despite these promising findings, the precise molecular mechanisms underlying SAL's anticancer action remain poorly understood. Here, we demonstrate that even at low concentrations (0.25-0.5 mM), SAL disrupts mitochondrial membrane potential and induces oxidative stress in Burkitt lymphoma. Further investigations uncovered that SAL shifts cellular metabolism from mitochondrial respiration to aerobic glycolysis. Additionally, metabolomic profiling identified SAL-induced arginine depletion as a key metabolic alteration. These findings provide new insights into SAL's multifaceted mechanisms of action and support its potential as an adjunctive therapy in cancer treatment.

Cyanobacterial extracts offer significant potential for the development of new natural antioxidants and biologically active compounds with applications in various industries. Data on the genus Tolypothrix are limited; therefore, the aim of the present study was to investigate the anticancer, antioxidant and anti-inflammatory activity of extracts prepared from strains of this genus. Cytotoxicity and anticancer activity were evaluated by in vitro tests with four cell lines using the MTT assay. The assessment of antioxidant activity was performed by the DPPH and ABTS methods in combination with the calculation of the total phenolic content. Anti-inflammatory activity was investigated using the LPS-stimulated macrophage model (RAW264.7) and subsequent measurement of the levels of secreted cytokines IL-6 and TNF-α. The lipid content and fatty acid composition of the non-polar extracts were determined by gas chromatography (GC). To elucidate the mechanism of cytotoxicity/anticancer action of the non-polar extracts, the effects of stearidonic acid, which was detected in four of the studied cyanobacterial strains, were additionally tested on the same cell lines. A molecular docking analysis was performed simulating the interaction between stearidonic acid and its target molecules and receptors (ALOX5, COX-2, NF-kB and PPAR-γ). In all cancer cell lines (but not in the normal one), dose-dependent cytotoxic effects were observed after exposure to different concentrations of non-polar Tolypothrix extracts. The most pronounced inhibitory effect was observed on the HT-29 cell line, with an IC50 value of 106.27 µg/mL. A dose-dependent antioxidant effect was established for all tested extracts, measured by both DPPH and ABTS methods. All non-polar extracts reduced the production of pro-inflammatory cytokines IL-6 and TNF-α in LPS-stimulated macrophages RAW264.7, and the effects were dose-dependent. Analysis of the fatty acid composition revealed 26 different fatty acids. Our conclusion is that the Tolypothrix strains exhibit anticancer, antioxidant, and anti-inflammatory activity and could be a promising source for the production of natural products.

The backbone of therapy for elderly patients with myelodysplastic syndromes and acute myeloid leukemia consists of hypomethylating agents 5-aza-2'-deoxycytidine (DAC) and 5-azacytidine (AZA). However, resistance frequently emerges during treatment. To investigate the mechanisms of resistance, we generated DAC-resistant variants of the acute myeloid leukemia cell lines, MOLM-13 and SKM-1, through their prolonged cultivation in increasing concentrations of DAC. The resistant cell variants, MOLM-13/DAC and SKM-1/DAC, exhibited cross-resistance to cytarabine and gemcitabine, but remained sensitive to AZA. Existing studies have suggested that the loss of deoxycytidine kinase (DCK) may play an important role in DAC resistance. DCK is critical for DAC activation, but the precise mechanisms of its downregulation remain incompletely understood. We identified a novel point mutation (A180P) in DCK, which results in acquired DAC resistance. Although the DCK mRNA was actively transcribed, the mutant protein was not detected in DAC-resistant cells. The transfection of HEK293 cells with the mutant DCK, combined with proteasomal inhibition, revealed rapid proteasomal degradation, establishing a mechanistic link between the A180P mutation and DCK loss, not previously described. This highlights the importance of also evaluating DCK at the protein and/or enzymatic activity levels in patients. The loss of functional DCK impairs the phosphorylation of deoxynucleosides, conferring resistance to DAC, gemcitabine, and cytarabine, but AZA, phosphorylated by uridine-cytidine kinase, remains effective and may represent a therapeutic alternative for patients with acquired DAC resistance.

Triple-negative breast cancer (TNBC) is an aggressive cancer characterized by a high risk of recurrence, invasiveness, metastatic potential, and poor prognosis. Tumor-associated macrophages (TAMs), particularly M2-like TAMs, contribute to TNBC progression by promoting an immunosuppressive tumor microenvironment (TME), highlighting the need for TME remodeling. This study aimed to evaluate the therapeutic efficacy of co-administering CL7, a CD300c monoclonal antibody that induces M1 macrophage polarization, and anti-PD-1, an immune checkpoint inhibitor, in TNBC. To establish a TNBC model, 4T1 cells were inoculated into the fourth left mammary gland of mice. CL7 and anti-PD-1 were intravenously administered twice a week. Flow cytometry and RT-PCR were performed to assess the immunotherapeutic effects, and lung metastases were evaluated by the Hematoxylin and Eosin staining of lung tissues. Tumor growth was significantly reduced in the combination treatment group (CL7 and anti-PD-1) compared to both the PBS and monotherapy groups. Additionally, the combination treatment increased M1 macrophages and activated CD8+ T and NK cells in the tumor, while significantly suppressing lung metastases. These findings suggest that the combination of CL7 and anti-PD- therapy has the potential to treat TNBC by remodeling the TME.

Metformin, caffeine, and dichloroacetate (DCA) have shown antitumor effects. The hypoxic tumor microenvironment can modulate drug response. We aimed to analyze the interaction of metformin with caffeine or DCA in lung cancer cells (HCC827) under normoxia and hypoxia conditions. Cell viability was evaluated using the crystal violet assay after individual and combined drug treatment under normoxia (21% O2) and hypoxia (1% O2) conditions. Combination effects were analyzed using isobolographic analysis. The results show that under normoxia conditions, the combination of metformin with DCA (γ = 0.98 ± 0.35, p > 0.05) or caffeine (γ = 0.90 ± 0.34, p > 0.05) revealed additivity. However, in hypoxia, both combinations exhibited significant antagonism, with γ values appearing greater than one for metformin + DCA (γ = 4.20 ± 1.44, p < 0.05) and metformin + caffeine (γ = 2.88 ± 0.90, p < 0.05). Hypoxia significantly alters the pharmacological interaction of metformin with caffeine or DCA, which could limit their combined therapeutic potential in hypoxic tumors despite metformin's activity in this environment. The importance of considering tumor oxygenation status in the design of combined therapies for lung cancer is emphasized.

Neuroblastoma (NB) is a malignant childhood tumour, which originates from neuroblasts with an incidence of approximately 15,000 new cases per year worldwide. Therapy-induced secondary tumorigenesis and the emergency of drug resistance in its high-risk (HR-NB) forms drive to a survival rate of <50%, despite aggressive treatments. Our recent research is focused on testing in vitro the effects of synthetized triphenyl phosphonium (TPP)-based bola amphiphilic nanovesicles (BPPBs) against both drug-sensitive and multi-drug-resistant (MDR) cancer cell lines. In the present study, BPPB demonstrated sub-micromolar IC50 values (0.4-0.9 µM) towards drug-sensitive HTLA 230, while 1.20-1.35 µM IC50 were determined on MDR HTLA ER. Noteworthily, we have demonstrated that BPPB triggers apoptosis of both NB cell populations. Additionally, since MDR NB cells (HTLA ER) are equipped with higher levels of antioxidants than sensitive ones (HTLA 230), the potential involvement of reactive oxygen species (ROS) in the cytotoxic action of BPPB was also investigated. Then, a novel analytical approach was applied to the results of cell viability and ROS monitoring for their better interpretation. Proper dispersion graphs and their best fitting nonlinear regression models were used to verify if the cytotoxic effects of BPPB could depend on BPPB concentrations, exposure times, and/or ROS generation, and if ROS increase could depend on BPPB concentrations and/or exposure times. A ROS-dependent mechanism was found in 24 h and 24/48 h treatments of HTLA ER and HTLA 230, respectively. Furthermore, the potential clinical development of BPPB as a new curative option for children affected by HR-NB was assessed by testing BPPB on astrocyte and neuron primary cell cultures, and analytical correlation studies were used to interpret the results. Notably, BPPB administration was sufficiently and well tolerated by neurons and astrocytes, respectively, allowing selectivity index values of up to 23.7. These in vitro results, associated with the low haemolytic activity of BPPB, pave the way for future in vivo investigations and, upon confirmation, for the possible development of BPPB as a novel therapeutic strategy to treat MDR HR-NB.

Aging is characterized by a progressive deterioration in physiological function and an increased susceptibility to age-related diseases, such as cancer. Monoclonal antibodies (mAbs) constitute a novel therapeutic approach aimed at addressing aging mechanisms such as cellular senescence, inflammaging, and immunosenescence. This text presents an overview of mAb methods aimed at the markers of aging and their potential application in cancer treatment. The mAbs can be categorized into senolytics, senescence-associated secretory phenotype (SASP) neutralizers, and immune checkpoint inhibitors, each targeting fewer aging-related pathways relevant to cancer therapeutic enhancement than the last. Translating promising preclinical evidence into enhanced efficacy and safety in cancer therapy presents challenges, particularly in older populations. This study examines the therapeutic efficacy of mAbs in the treatment of cancer and age-related disorders, focusing on their current and future roles in oncology practice.

Cisplatin (cis-diamminedichloro-platinum; CDDP) is a chemotherapeutic agent that frequently induces peripheral neuropathy characterized by mechanical allodynia. Herein, we aimed to determine the effects of valproic acid (VPA) on cisplatin-induced mechanical allodynia in rats and elucidate the underlying mechanisms. A single administration of VPA (150 mg/kg) transiently suppressed CDDP-induced mechanical allodynia, correlating with serum VPA concentrations. Repeated VPA administration before or after the onset of CDDP-induced mechanical allodynia significantly attenuated allodynia even after VPA discontinuation, suggesting fundamental treatment potential. Mechanistically, CDDP increased the expression of neurokinin 1 receptor (NK1R) mRNA in the dorsal horn of the spinal cord, and this increased expression was suppressed by repeated VPA administration. Treatment with an NK1R antagonist alleviated CDDP-induced mechanical allodynia, indicating the involvement of NK1R in allodynia. In vitro assays revealed that VPA did not affect the cytotoxicity of CDDP in Walker 256 cells, suggesting that VPA does not interfere with the antitumor activity of CDDP. Overall, repeated VPA administration may fundamentally ameliorate CDDP-induced peripheral neuropathy by suppressing the CDDP-induced increased NK1R expression without compromising the antitumor effects of CDDP. These findings provide insights into the potential use of VPA as a therapeutic agent for managing CDDP-induced peripheral neuropathy.

In recent years, the incidence rate of cancer has been on the rise all over the world, and the age of cancer patients has shown a younger trend, which seriously endangers patients' health. Edible/medicinal mushrooms have not only become a new source of nutritional supplements but have also emerged as a promising adjunct to conventional medicine, either by directly or indirectly killing tumor cells and enhancing immunity, or through their use in conjunction with modern cancer therapies to enhance their efficacy or reduce their side-effects, improving patients' quality of life. Although the anti-cancer potential of edible and medicinal mushrooms has been widely studied in the past, this review focuses on the most recent literature from the last five years, providing an up-to-date and comprehensive summary of the current findings. In this review, we aim to analyze the anti-cancer effects of edible/medicinal mushrooms, including Schizophyllum commune, Trametes versicolor, Grifola frondosa, Ganoderma lucidum, Lentinula edodes, Laetiporus sulphureus, Boletus edulis, and Phellinus igniarius, as well as their potential anti-cancer mechanisms, providing strong theoretical support for the further development of edible/medicinal mushroom anti-cancer products.

Isorhamnetin (ISO) is a natural flavonoid compound that has become a main research topic in recent years due to its multitargeted antitumor properties. In this paper, we systematically review the molecular basis of the inhibition of malignant tumors by ISO, including through the regulation of the cell cycle, PI3K/AKT/mTOR pathway, MAPK pathway, apoptosis/autophagy-related pathways, and the tumor microenvironment. We also explore its synergistic effects with chemotherapy/targeted therapies and its potential for clinical translation. Experimental studies have shown that ISO can not only directly inhibit tumor proliferation by inducing tumor cell cycle arrest, mitochondria-dependent apoptosis, and endoplasmic reticulum stress, but also enhance antitumor immune responses by regulating the immune microenvironment. Pharmacokinetic studies have shown that novel delivery systems, such as nano-formulations, significantly enhance the bioavailability of ISO. Notably, ISO has demonstrated unique advantages in attenuating the nephrotoxicity of chemotherapeutic agents, protecting normal cells, and reversing tumor resistance. However, the optimal dosing regimen, dose-effect relationship, and cross-species applicability need to be further validated by large-scale preclinical animal experiments and clinical trials. This paper provides a theoretical basis for the development and application of ISO for the treatment of malignant tumors and highlights its potential value in animal models.

Ovarian cancer is a highly prevalent cancer among women with a high risk for relapse and drug resistance. Seventy eight percent of women diagnosed with ovarian cancer live for at least one year after diagnosis. Hyptolide, a natural compound, has been shown to act as an anti-inflammatory and antibacterial agent, and latest research shows that it acts as an anticancer agent. These properties indicate that hyptolide may be a potential treatment option for ovarian cancer, including chemoresistant cases; however, its effects in chemoresistant ovarian cancer have not yet been demonstrated, and the mechanisms underlying its induction of cell death remain unclear.

Chemotherapy-induced taste alterations are a prevalent but frequently under-recognized complication with significant nutritional and psychosocial consequences. In this letter, we offer a critical appraisal of the recent study by Köksal et al., highlighting key gaps that limit its translational applicability. We emphasize the importance of accounting for comorbid conditions, psychosocial impacts, and treatment-specific factors-such as variability among chemotherapeutic agents and adjunct medications. Additionally, we advocate for a multidisciplinary approach to better address dysgeusia in clinical oncology. Our commentary aims to broaden the clinical perspective on dysgeusia and support more comprehensive supportive care strategies.

Cancer is a medical problem that has been difficult to overcome on a global scale. Owing to the sharing of single or multiple genes or regulatory modules, cancer treatment often faces severe challenges. The core of network pharmacology lies in constructing human disease gene regulation networks and multi-pharmacology network. With the continuous updating and iteration of new technologies, it is helpful for us to systematically understand the occurrence and development mechanism behind complex diseases and elucidate the pharmacological mechanisms from the perspective of biological network balance. This review aims to clarify the application of network pharmacology in exploring the pharmacological treatment mechanism of natural products, drug repositioning, and new technology combinations in the context of complex pathogenesis of cancer, so as to help realize the full potential of network pharmacology. Additionally, we discuss the future development of network pharmacology to guide clinical diagnosis and treatment.

Immune-related neuropathy (irNeuropathy) and myositis (irMyositis) are the most common neurologic adverse events (irAE-n) associated with immune checkpoint inhibitors. Although case reports suggest benefits of complement inhibitors, the role of complement activation in irAE-n is understudied.

For patients with advanced non-small cell lung cancer (NSCLC) harboring sensitive epidermal growth factor receptor (EGFR) mutations, guidelines prioritize the use of third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs), which offer higher objective response rate (ORR), longer progression-free survival (PFS), and better quality of life. However, due to the low proportion of elderly patients enrolled in clinical trials, the existing evidence is insufficient to fully guide clinical practice. This review examines the efficacy and safety differences of third-generation EGFR-TKIs as monotherapy or in combination in the elderly NSCLC by integrating subgroup analyses or pre-specified research objectives from prospective and retrospective studies. The results show that third-generation EGFR-TKIs have comparable efficacy in elderly patients to younger populations and are well-tolerated. Although combination therapies may extend survival time, the associated increased toxicity necessitates careful risk-benefit assessment.
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The cardiotoxicity of immune checkpoint inhibitors (ICIs) has garnered significant clinical attention due to its high mortality rate. However, limited clinical research and inconsistent results have hindered a comprehensive understanding of this issue. This study seeks to elucidate gender and age differences in cardiac-related adverse reactions, aiming to offer scientific evidence to inform clinical practice.

Resistance to v-raf murine sarcoma viral oncogene homolog B1 (BRAF) plus mitogen-activated protein kinase kinase (MEK) inhibition (BRAFi+MEKi) in BRAFV600E-mutant gliomas drives rebound, progression, and high mortality, yet it remains poorly understood. This study addresses the urgent need to develop treatments for BRAFi+MEKi-resistant glioma using preclinical mouse models and patient-derived materials. BRAFi+MEKi reveals glioma plasticity by heightening cell state transitions along glial differentiation trajectories, giving rise to astrocyte- and immunomodulatory oligodendrocyte (OL)-like states. PD-L1 upregulation in OL-like cells links cell state transitions to immune evasion, possibly orchestrated by Galectin-3. BRAFi+MEKi induces interferon response signatures, tumor infiltration, and suppression of T cells. Combining BRAFi+MEKi with immune checkpoint inhibition enhances survival in a T cell-dependent manner, reinvigorates T cells, and outperforms individual or sequential therapies in mice. Elevated PD-L1 expression in BRAF-mutant versus BRAF-wild-type glioblastoma supports the rationale for PD-1 inhibition in patients. These findings underscore the potential of targeting glioma plasticity and highlight combination strategies to overcome therapy resistance in BRAFV600E-mutant high-grade glioma.

Immune checkpoint inhibitor (ICI) have demonstrated efficacy in treating various cancers by modulating the immune system, but this can lead to immune-related adverse events (irAEs), including myocarditis. ICI-associated myocarditis is a rare but highly lethal irAE with a short mean time to onset, and difficult to diagnose early due to nonspecific symptoms and lack of biomarkers. This review highlights the need for improved recognition and management of ICI-associated myocarditis, summarizing recent advances in immunology, pathology, and biomarker research. We discuss the epidemiology, clinical features, immunological mechanisms, and roles of biomarkers in diagnosis and risk stratification. Traditional biomarkers like cTnI and hs-cTnT are sensitive but lack specificity, while emerging biomarkers like miR-155 show tissue specificity. Inflammatory markers such as NLR and CRP aid prognosis but have limited diagnostic value.

Glioblastoma is the most predominant type of brain tumor, and resistance to medication has hampered the effectiveness of chemotherapy for gliomas. Acyclic monoterpene alcohol, linalool, has a range of pharmacological properties. The present study aimed to evaluate the impact of linalool and its nanoformulation on glioblastoma cell proliferation. DFT and ADMET analyses were used to initially assess the physiochemical characteristics of linalool and the produced silver nanoconjugates, LN@AgNPs. STRING database and Gene Expression Profiling Interactive Analysis (GEPIA) were used to narrow the 6 genes involved in glioblastoma and underwent for molecular docking study. Using AutoDock Vina 1.5.7, ligands were docked to the interaction site of selected targets. Top scored complexes PD-L1/Ligands and PTEN/ligands were simulated using molecular dynamics. The results revealed that LN@AgNPs produced a more stable complex, because metallic bonds are more robust and durable than hydrogen bonds, which give metals their distinctive strength and stability. To confirm the cytotoxicity of the compound against GBM cell line SF-767, linalool and LN@AgNPs were evaluated by in vitro study to check the expression at the IC50 concentration of top scored selected genes. The results indicated that the cytotoxic effects of linalool and LN@AgNPs were concentration dependent. In the SF-767 cancer cell line, linalool and LN@AgNPs with IC50 (33.14 µg/mL and 22.12 µg/mL respectively) values downregulated PD-L1 expression and increased PTEN expression. In conclusion phytocompounds conjugated with AgNPs increased cytotoxicity and inhibition index in glioblastoma cells. Therefore, LN@AgNPs may be a viable option for cancer treatment.

Nigella sativa L. widely used spice cum medicinal plant in Asia and the middle east, is renowned for its seeds and oil which possess both culinary and therapeutic purposes. Its rich content of bioactive compounds, including metabolites and phenolics, with Thymoquinone, a monoterpene quinone, emerging as key therapeutic compound significantly consideration for its various pharmacological activity with lower toxicity compared to conventional chemotherapy. This study evaluated the anticancer potential of thymoquinone isolated from N. sativa L., through cytotoxicity and In Silico studies. Seeds from 38 accessions were collected across the country and screened for Thymoquinone content using HPTLC with the highest concentration identified in Ajmer Nigella 13 (247.60mg 100gm-1) accession. In Vitro MTT assay of Thymoquinone in human myelogenous leukemia (K562) cells demonstrated significant dose and time dependent cytotoxicity confirming Thymoquinone's potential as a promising therapeutic candidate for leukemia and other cancer.