Osteosarcoma (OS), the most common primary malignant bone tumor, is associated with a high risk of recurrence and metastasis, leading to poor prognosis. This study explored the potential use of drug repositioning by investigating nortriptyline hydrochloride (NTP) in osteosarcoma treatment. NTP, a classic tricyclic antidepressant used to treat psychiatric disorders, has been shown to have antitumor activity against several cancer types. We investigated the inhibitory effects of NTP on OS cell proliferation and migration. The anticancer activity of NTP was evaluated in terms of cell viability, chemical rescue by cell death inhibitors, lactate dehydrogenase (LDH) release, cytoskeletal staining, and cell cycle analysis. NTP inhibited the proliferation of OS cells and induced G0/G1 phase cell cycle arrest in a dose-dependent manner. The IC50 values of NTP were 24.2 μM and 15.8 μM for U2OS and MG-63 cell proliferation, respectively. Chemical rescue using cell death inhibitors and LDH release assays showed that the anticancer effects of NTP was mainly attributed to the inhibition of cell proliferation. Additionally, NTP inhibited cell migration, disrupted actin filament formation, and altered intracellular distribution. Furthermore, NTP retained growth inhibitory activity in doxorubicin-resistant OS cells. NTP may serve as a novel therapeutic agent for preventing OS growth and metastasis.

Design, synthesis and anti-bladder cancer activity of novel dihydroartemisinin-ibuprofen hybrids.

Salt form and phosphate modification of an SN-38-nitrogen mustard conjugate: Overcoming water solubility limitations, combined efficacy, and broadened antitumor Spectrum.

Dual BRD4/AKT inhibition overcomes c-MYC-driven resistance in metastatic castration-resistant prostate cancer.

Cannabigerol (CBG), a non-psychoactive phytocannabinoid derived from Cannabis sativa, has attracted increasing attention owing to its antibiotic, anti-inflammatory, and anticancer properties. However, its therapeutic potential in pancreatic cancer remains unknown. In this study, we demonstrated for the first time that CBG exerts a potent antiproliferative effect on human pancreatic cancer cells by inducing cell cycle arrest in the G1 phase and promoting programmed cell death. Transcriptomic profiling revealed that CBG significantly modulates the gene networks involved in apoptosis and ferroptosis. Consistent with these findings, CBG treatment upregulated apoptosis-associated proteins, such as cleaved caspase-3, caspase-9, and PARP1, and increased the proportion of apoptotic cells. CBG triggered robust activation of the unfolded protein response (UPR), with a marked increase in the transcriptional levels of endoplasmic reticulum (ER) stress-related genes. Mechanistically, CBG activated the IRE1α-XBP1 axis, a key branch of the UPR, as evidenced by enhanced XBP1 mRNA splicing. Inhibition of IRE1α by the small-molecule inhibitor 4μ8C substantially mitigated CBG-induced cytotoxicity, emphasizing the central role of ER stress pathways in the mechanism of CBG's action. Moreover, CBG modulated the expression of ferroptosis-related genes and proteins, such as DDIT3, NFE2L2, and HMOX1, and their respective protein products, CHOP, NRF2, and HO-1. These findings reveal a novel mechanism by which CBG concurrently induces apoptosis and ferroptosis via ER stress-driven activation of the IRE1α pathway, supporting its potential as a therapeutic agent targeting ER stress-related vulnerabilities in pancreatic cancer.

Colorectal cancer (CRC) remains difficult to treat due to challenges in early detection and the development of therapeutic resistance. Dopamine receptor D2 (DRD2) plays a critical role in regulating cell proliferation and apoptosis in various solid tumors. Given the relatively high levels of dopamine in the gastrointestinal tract, colorectal tumors may be particularly susceptible to DRD2-mediated signaling. In this study, we evaluated the anticancer activity of a newly synthesized DRD2 antagonist, SD2-2305, and investigated its underlying mechanisms in human CRC cell lines HCT116 and HT-29. SD2-2305 reduced cell viability in a time- and dose-dependent manner. Induction of apoptosis was confirmed by Annexin V/PI staining and immunoblot analysis, with activation of caspase-3, caspase-7, and caspase-9, although no significant changes were observed in the expression of Bcl-2 family proteins. Furthermore, SD2-2305 induced G1 phase cell cycle arrest, accompanied by downregulation of Cyclin A, Cyclin B, CDK1, and CDK2, and upregulation of p21. While key survival pathways (JAK2/STAT3, PI3K/Akt, and MAPK) remained relatively unaffected, SD2-2305 modulated growth factor receptors post-transcriptionally, decreasing HER2/ErbB2 and increasing TGF-beta receptor 1 expression. Collectively, these findings demonstrate that the DRD2 antagonist SD2-2305 exerts potent anticancer effects through the induction of cell cycle arrest and apoptosis, and suggest that the anticancer activity of SD2-2305 is associated with coordinated modulation of growth factor receptor signaling and cell-cycle regulators in CRC cells.

Novel β-carboline quaternary ammonium salts: design, synthesis, structural insight and antitumor activity.

Dacarbazine (DTIC) is a crucial drug for treating melanoma, but resistance to it poses a significant challenge to effective chemotherapy. Photodynamic therapy (PDT), a minimally invasive, repeatable, and highly selective anti-cancer treatment, has shown promise in recent studies as a potent modulator of chemotherapy sensitivity in different cancerous cells. This investigation aims to explore the effect of photodynamic treatment on the DTIC sensitivity of melanoma cells. The SKMEL-3 melanoma cells were treated with PDT and DTIC, separately or in combination. The toxicity consequences of these treatments were studied using MTT test. This assay was used to analyze the cytotoxic effects of these treatments, and increased DTIC sensitivity was observed in SK-MEL-3 cells following pre-treatment with PDT. Additionally, flow cytometry analysis showed sub-G1 phase cell cycle arrest and increased apoptosis in all treatment groups. Alterations in the expression levels of caspases (3, 8, 9) and Bcl-2 genes further confirmed that apoptosis was more pronounced in the combination group. Moreover, combining PDT with DTIC significantly downregulated the expression of PI3K, AKT, and mTOR, while upregulating PTEN. Our data suggest that all mentioned treatments significantly reduce cell migration by downregulating MMP-2 and MMP-9 and decrease clonogenicity by downregulating SOX2 and OCT4 in SK-MEL-3 cells, with these effects being more evident after combination treatment. In conclusion, our findings highlight the potential of PDT pre-treatment to enhance DTIC sensitivity in SK-MEL-3 cells and suggest that the combination therapy is a promising strategy for further research in melanoma treatment.

This study explores programmed cell death (PCD)-related genes in osteosarcoma through bioinformatics and experimental validation. Analysis of datasets from the GEO and TCGA databases identified 5,327 differentially expressed genes (DEGs), among which 294 overlapped with PCD-related genes. LASSO regression analysis identified six hub genes, and five of these (CIB1, CREB3L1, IL6R, TGFβ2, and TNFRSF10C) were further validated in osteosarcoma tissues. Notably, CIB1 exhibited significantly elevated expression and was selected for in-depth analysis. CIB1 downregulation inhibited osteosarcoma cell proliferation and invasion by inducing apoptosis and causing G2/M phase cell cycle arrest, and was associated with increased p53 expression, decreased phosphorylation of Akt and STAT3, and altered BCL2/BAX ratios, suggesting involvement of these pathways in the observed effects. In vitro experiments confirmed the tumor-suppressive role of CIB1 inhibition. These findings highlight CIB1 as a promising therapeutic target for osteosarcoma treatment.

Cell cycle (CC) dynamics are reflected in diverse T cell processes such as TCR activation, expansion, contraction, differentiation, senescence, anergy, and exhaustion; linking CC behaviors to functional and dysfunctional T cell states in development and disease. Progression through CC checkpoints is also tightly linked to cell fate decisions across development. Yet, much remains unknown about the connection between CC sensing and T cell differentiation programs. To disentangle the relationship across T cell state, time-since-activation, receptor signaling, division, and CC, we leverage high-throughput single-cell mass cytometry for parallel measurement of these diverse biological states. By modulating CC progression and receptor signaling with inhibitors as well as tonic signaling Chimeric Antigen Receptor (CAR) models of T cell exhaustion, we reveal that earlier G1/S CC programs crosstalk with receptor signaling to control T cell fate, and that exhaustion programs are downstream to aberrant, S-G2 phase CC arrest signatures in tonic CAR signalingin vitro,in situ, and in vivoacross human cancers in association with CD8 T-lymphocyte dysfunction.

Novel peptide Aurein1.2 derivative induces cytotoxicity in cervical cancer SiHa and HeLa cells by apoptosis and cell cycle arrest.

Breast cancer ranks as the foremost cause of death among women worldwide. Despite the availability of various treatment options such as chemotherapy, radiotherapy, and hormone therapy, these current strategies are often ineffective and thereby, there is a constant necessity to explore new therapeutic avenues with minimal side effects and enhanced efficacy. The application of cell-based therapy and the use of stem cells or their derivatives in treating diseases, including cancer, have become well established. Herein, we aimed to investigate the impact of the secretome of human amniotic mesenchymal stem cells (hAMSCs) on MDA-MB-231 cancer cells (with a mutant p53 R280K background) focusing on the p53/MDM2/p21/ATM/ATR/PUMA/Bax/Caspase3 signaling pathways. To achieve this, we developed a co-culture system utilizing 6 well plates transwell. After 72h, cell death and cell cycle arrest in hAMSCs-treated MDA-MB-231 cells were assessed by analyzing the aforementioned signaling pathways using Western blot and flow cytometry. The exposure time for MTT assay was 48h, and for DAPI staining, it was 24h. Our results revealed an increase in the expression levels of ATM, ATR, CHK2, p53, p-p53, PUMA, Bax, cleaved caspase 3, p21, RB, and p-RB, alongside a reduction in MDM2 expression. These findings suggest that hAMSCs secretome promotes cell death and induces S phase cell cycle arrest in MDA-MB-231 cells, suggesting its potential as a novel approach in cancer therapy.

Gap junctions play a crucial role in intercellular communication, participating in both physiological and pathological processes. Although artificial gap junctions have been developed, their physiological functions beyond basic intercellular communication remain largely unexplored. Herein, we report a functional artificial gap junctional channel system constructed via electrostatic co-assembly of an amphiphilic transmembrane channel and a hydrophilic extracellular channel. The efficient ion transport capability of the amphiphilic channel, coupled with the extensive aggregation of the hydrophilic module within the intercellular gap, enables the formation of stable intercellular junctions. Similar to natural gap junctions, these artificial channels not only mediate intercellular ion transport but also induce G1 phase cell cycle arrest and inhibit the proliferation of hepatocellular carcinoma cells. This work provides a new strategy for intervening in cell-cell communication and offers a potential therapeutic avenue for cancer and gap junction-related diseases.

ABSTRACT Gap junctions play a crucial role in intercellular communication, participating in both physiological and pathological processes. Although artificial gap junctions have been developed, their physiological functions beyond basic intercellular communication remain largely unexplored. Herein, we report a functional artificial gap junctional channel system constructed via electrostatic co‐assembly of an amphiphilic transmembrane channel and a hydrophilic extracellular channel. The efficient ion transport capability of the amphiphilic channel, coupled with the extensive aggregation of the hydrophilic module within the intercellular gap, enables the formation of stable intercellular junctions. Similar to natural gap junctions, these artificial channels not only mediate intercellular ion transport but also induce G1 phase cell cycle arrest and inhibit the proliferation of hepatocellular carcinoma cells. This work provides a new strategy for intervening in cell–cell communication and offers a potential therapeutic avenue for cancer and gap junction‐related diseases.

Flavonoids comprise an exclusive class of biomolecules with extensive therapeutic features. Rutin is one of the flavonoids that has antioxidant, anticancer, and other pharmacological actions, but its clinical use is deterred by poor solubility, poor bioavailability, and incomplete absorption. Development of nanotechnology-based delivery platforms is a promising solution to counter these issues. We evaluated the antioxidant and anticancer properties of nanocrystals and spanlastic nanoparticles of rutin against the human breast adenocarcinoma cell line MCF-7 to establish effective delivery methods with improved therapeutic efficacy. The physicochemical characteristics of the nano-formulations were investigated through particle size and zeta potential measurement, Fourier Transform Infrared spectroscopy (FTIR), transmission electron microscopy (TEM), scanning electron microscopy (SEM), electronic bandgap energy, and dissolution behavior. Antioxidant activity was investigated through DPPH and ABTS radical scavenger assays. Anticancer potential was established through a viability assay, cell cycle analysis, dual labeling with annexin-V/propidium iodide (PI) (using fluorescence-activated flow cytometric methods), and Caspase 3 activity. Rutin spanlastic nanoparticles showed a considerably smaller particle size, homogeneous dispersion, and negative zeta potential, indicating stability. Rutin spanlastic nanoparticles exhibited greater antioxidant activity compared with free rutin and rutin nanocrystals, as manifested through stronger inhibition of the viability of MCF-7 cells, stronger induction of apoptosis (annexin-V/PI double staining and Caspase 3 activity), and significant G1/0 phase cell cycle arrest. These observations imply an increased solubilization and elastovesicular behaviour of spanlastic nanoparticles with enhanced bioactivity of rutin. In conclusion, rutin spanlastic nanoparticles are an efficient delivery vehicle compared to rutin nanocrystals or free rutin in amplifying both antioxidant and anticancer activity, hence warranting further in vivo experiments to treat breast carcinoma.Graphical abstract

Sagittaria sagittifolia polysaccharide extract attenuates inflammation and senescence through dual involvement of TLR4/NF-κB and SIRT1/NF-κB in vivo and in vitro models of COPD.

Glioblastoma multiforme (GBM) is a lethal and fast-growing brain cancer that is difficult to treat with standard medical interventions. GBM tumors often overexpress cyclin-dependent kinase 9, in complex with cyclin T1, and thus, it represents a promising target for therapeutic intervention. In this study, we employed a structure-based virtual screening approach for a curated library of 6,059 bis-pyridyl compounds from PubChem to identify potential CDK9/T1 inhibitors. Subsequent in vitro ADP-Glo assay led to the identification of GNE-3511 as a potent CDK9/T1 inhibitor with an IC50 of 0.064 μM. GNE-3511 also inhibited CDK7/cyclin H with an IC50 of 0.12 μM. In U-87 MG and T98G glioblastoma cells, GNE-3511 exhibited cytotoxicity with a GI50 of 3.4 and 5.0 μM, inducing G2/M phase cell cycle arrest and promoting early apoptosis. Treatment with GNE-3511 significantly reduced the expression of the anti-apoptotic markers BCL-2, SURVIVIN and drug resistance markers (ABCB1 and ABCG2) in a dose-dependent manner, and downregulated glioma stem cell population/markers (CD44, CD90+, or CD133+ and BMI-1) and sphere formation abilities. Oral administration of GNE-3511 at 20 mg/kg (twice daily) demonstrated significant anti-tumor efficacy and improved survival in both U-87 MG and T98G xenograft/orthotopic mouse models. Collectively, these findings highlight GNE-3511 as a promising lead candidate for the development of GBM therapeutics.

In silico discovery and biological evaluation of a novel selective HDAC8 inhibitor featuring 1H-pyrazolo[3,4-b]pyridine scaffold.

ABSTRACTInsulin substantially promotes the growth of malignant cells that overexpress the insulin receptor (INSR), and insulin excess has been recognised as a cancer‐promoting factor in patients. Interferon‐induced transmembrane protein 1 (IFITM1) is also overexpressed in various cancers. In this study, we investigate the association between insulin signalling‐induced IFITM1 expression and multiple myeloma (MM) aggressiveness. We observed that expression of both INSR and IFITM1 was significantly elevated in symptomatic MM patients compared with those with monoclonal gammopathy of undetermined significance (MGUS) and smouldering MM (SMM). Notably, IFITM1—but not INSR—expression correlated with prognosis following autologous stem cell transplantation and bortezomib‐based induction therapy. Further analysis revealed that IFITM1 expression in bone marrow plasma cells was associated with the concentrations of insulin and insulin‐like growth factor 2 (IGF‐II) in the bone marrow microenvironment. Insulin and IGF‐II enhanced MM cell proliferation through IFITM1 upregulation, whereas suppression of IFITM1 abrogated the proliferative effects of these ligands. Moreover, insulin and IGF‐II attenuated apoptosis and the inhibition of cell migration induced by the proteasome inhibitors (PIs) bortezomib and carfilzomib, and these effects were reversed by IFITM1 knockdown. The ability of insulin to reduce bortezomib‐induced apoptosis and G2/M phase cell cycle arrest was likewise dependent on IFITM1 expression. Collectively, these findings suggest that insulin‐induced IFITM1 plays a pivotal role in MM progression and resistance to bortezomib, highlighting IFITM1 as a potential prognostic biomarker and therapeutic target.

Three new Zn(II) coordination compounds derived from chrysin and 1,10-phenanthroline were synthesized using microwave-assisted methodology: a mononuclear complex ( 1 ), a two-dimensional coordination polymer ( 2 ), and a tetranuclear cluster ( 3 ). Fine-tuning of reaction parameters enabled selective access to these distinct architectures, with single-crystal X-ray diffraction confirming the structures of 1 and 3 . Positive-ion nanospray mass spectrometry showed that complexes 1 and 2 predominantly generate well-defined mononuclear Zn–chry–phen units upon ionization, a behavior consistent with the formation of such units under the experimental conditions, whereas cluster 3 undergoes extensive fragmentation into Zn–phen-based dicationic species, limiting biological evaluation to complexes 1 and 2 . Both compounds displayed enhanced, though moderate, radical-scavenging activity relative to free chrysin, consistent with electronic modulation and stabilization of phenoxyl radicals upon metal coordination. Their anticancer properties were assessed in vitro against human melanoma (A375), hepatocellular carcinoma (HepG2), and non-tumoral keratinocyte (HaCaT) cell lines. Complexes 1 and 2 exhibited pronounced time- and dose-dependent cytotoxicity, with IC 50 values in A375 and HepG2 markedly lower than those of free chrysin and comparable to phen. Cytotoxicity in HaCaT keratinocytes occurred within the same micromolar range, indicating modest selectivity while still providing meaningful insight into the biological behavior of Zn(II)–chrysin–phen systems. Mechanistic studies indicated S phase cell cycle arrest and increased reactive oxygen species (ROS) generation, suggesting oxidative stress as a key contributor to cytotoxicity against the tumor cell-lines. Overall, these findings highlight the versatility of microwave-assisted synthesis for generating structurally diverse Zn(II)–flavonoid architectures and advance understanding of their coordination chemistry and structure–activity relationships. • MWAS yields three distinct Zn(II)–chrysin–phen complexes. • Reaction control enables selective crystalline architectures. • Complexes 1–2 form stable mononuclear Zn–chry–phen units. • Complexes 1–2 show notable cytotoxicity in cancer cell lines. • ROS increase and S phase arrest drive cytotoxic effects.