Towards a dual copper(II) and iron(III) transmetalation strategy for an anticancer application with the deferasirox chelator.

Although β‑glucan exhibits various biological activities, the anticancer mechanisms of a low‑molecular‑weight β‑glucan isolated from Aureobasidium pullulans (LMW‑AP‑FBG) in colorectal cancer remain unclear. Therefore, this study investigated the anticancer potential of LMW‑AP‑FBG in human colon cancer cells. Treatment of SW480 cells with LMW‑AP‑FBG resulted in a significant reduction in cell viability in a concentration‑ and time‑dependent manner, with half‑maximal inhibitory concentrations (IC50) of 557.2, 497.4 and 300.6 µg/ml at 24, 48 and 72 h, respectively. Apoptotic cell death was evidenced by increased caspase‑3/7 enzymatic activity and proteolytic cleavage of caspase‑3, ‑7, ‑8, ‑9 and poly (ADP‑ribose) polymerase. Notably, pharmacological inhibition of caspases using the pan‑caspase inhibitor Z‑VAD‑FMK only partially restored cell viability, suggesting the involvement of caspase‑independent cell death mechanisms. Mitochondrial dysfunction was further indicated by dissipation of mitochondrial membrane potential, cytosolic accumulation of cytochrome c, and downregulation of the anti‑apoptotic protein Bcl‑2, collectively supporting activation of the intrinsic apoptotic pathway. In parallel, the expression of autophagy‑related proteins was markedly increased, implying concomitant induction of autophagic processes. Mechanistically, LMW‑AP‑FBG suppressed the PI3K/AKT/mTOR signaling axis, a central regulator of cell survival and autophagy. Collectively, these findings demonstrate that LMW‑AP‑FBG exerts anticancer effects in SW480 colon cancer cells through coordinated activation of apoptotic and autophagy‑associated pathways, highlighting its potential as a bioactive anticancer agent and warranting further in vivo validation.

Inhibition of PRMT5 sensitizes B-cell non-Hodgkin lymphoma cells to both intrinsic and extrinsic apoptotic cell death.

A smart pH-responsive and sialic acid targeted hybrid nanoparticles for precise chemo-herbal delivery in lung cancer.

LMT328, a sulfiredoxin inhibitor, induces preferential cancer cell death and tumor regression via oxidative stress.

The complex mechanistic network of periprosthetic osteolysis: Integration from inflammatory response and tissue stress to signaling pathways.

Cis-trans divergence in the regulatory architectures of MYBL2 and MYB underlies distinct transcriptional networks in immunometabolic traits.

Design, synthesis, and anti-glioblastoma multiforme evaluation of novel multikinase inhibitors via a cyclization strategy with potent FAK inhibition.

Cyphenothrin disrupts the integrity of porcine trophectoderm and uterine luminal epithelial cell lines by inducing mitochondrial dysfunction and oxidative stress.

Given their critical roles in tumor progression and hypoxia adaptation, concurrent inhibition of carbonic anhydrase IX (hCA IX) and vascular endothelial growth factor receptor-2 (VEGFR-2) is a viable therapeutic approach. This study rationally developed, synthesized, and biologically assessed a novel class of thiazolidinedione-benzenesulfonamide hybrids as possible dual hCA IX/VEGFR-2 inhibitors. A number of agents, including 4a, 4b, 4e, 4g, 6a, and 6b, showed strong hCA IX inhibition (KI = 15.0-37.9 nM), outperforming the reference inhibitor acetazolamide (KI = 25 nM) and displaying better selectivity indices. Moreover, these substances efficiently suppressed VEGFR-2, with IC50 values ranging from 0.055 to 1.080 µM. Under both normoxic and hypoxic conditions, biological evaluation demonstrated strong anti-proliferative activity against colorectal cancer cell lines (HT-29 and HCT-116). Compound 4g stood out as the most promising candidate among the investigated derivatives, showing greater activity to 5-fluorouracil during hypoxia and comparable potency under normoxia (IC50 = 5.89 vs. 26.66 µM). In hypoxic conditions, 4g significantly enhanced the cytotoxicity of 5-fluorouracil, increasing its activity by more than sevenfold. 4g caused cell-cycle arrest at the G1/G2/M phases, raised pro-apoptotic markers (caspase-3, caspase-9, and BAX), downregulated the anti-apoptotic protein Bcl-2, and dramatically enhanced apoptotic cell death (total apoptosis: 37.78%), according to mechanistic studies. The persistent binding of 4g inside the zinc-containing active site of hCA IX and the ATP-binding pocket of VEGFR-2 was validated by molecular docking and molecular dynamics simulations. Additionally, favorable pharmacokinetic and drug-likeness features were shown by in silico ADME research. All of these results point to compound 4g as a promising mechanism-based dual VEGFR-2/hCA IX inhibitor with strong anti-colorectal cancer action, especially in hypoxic tumor microenvironment circumstances.

Dual organelle targeting type I/II photosensitizer triggers ferroptosis-like/apoptosis for photodynamic immunotherapy.

Pulsed electromagnetic fields (PEMF) can be used to improve the efficacy of chemotherapeutic agents, such as doxorubicin (DOX). DOX induces mitotic slippage, leading to cell death in various cancers including breast cancer. Herein, we investigated whether PEMF exposure enhances DOX-induced mitotic slippage and subsequent cell death in breast cancer cells. DOX-treated MDA-MB-231 breast cancer cells were stimulated with a 60 min PEMF session three times daily. Cell viability was assessed using the trypan blue exclusion assay. Cell cycle distribution and polyploidy were assessed using flow cytometry, and the morphological features of mitotic slippage were observed microscopically. Western blotting and confocal microscopy were used to evaluate the key molecules involved in G2/M transition, mitotic transition, and caspase-mediated cell death. DOX treatment for three days induced mitotic slippage including cell enlargement, polyploidy, and multinucleation, which was further enhanced by PEMF exposure. DOX treatment also induced CDK1 activation, histone H3 dephosphorylation, and survivin and PLK1 downregulation, which were further increased by PEMF exposure. In addition, CDK1 inhibition reduced mitotic slippage phenotypes and suppressed caspase-2-dependent cell death, resulting in partial restoration of cell viability in the DOX+PEMF group. PEMF promotes DOX-induced mitotic slippage and subsequent caspase-2-dependent cell death in MDA-MB-231 cells by modulating cell cycle checkpoint regulators such as CDK1, survivin, and PLK1. These findings suggest that PEMF may serve as a novel adjuvant to potentiate the anticancer efficacy of DOX by increasing DOX-induced mitotic slippage.

Cancer cells proliferate uncontrollably, and a major challenge in cancer research is to identify strategies that selectively eliminate cancer cells while sparing normal cells. Squamous cell carcinoma antigen recognized by T cells 1 (SART1) was originally identified as a carcinoma-associated antigen and is frequently overexpressed in cancer cells. Recently, SART1 has been identified as a microtubule-associated protein required for spindle pole formation and cell division. Here, we show that partial depletion of SART1 by RNA interference selectively disrupts mitotic spindle assembly and induces cell death in cancer cells. siRNA-mediated knockdown reduced SART1 protein levels comparably in multiple human cell types, yet spindle defects and apoptotic cell death were observed in HeLa and U2OS cancer cells but not in non-transformed BJ fibroblasts or RPE1 epithelial cells. Consistent with this cancer-selective sensitivity, SART1 depletion markedly suppressed oncogene c-Myc-induced transformation of RPE1 cells without impairing the growth of untransformed cells. These results demonstrate that partial depletion of SART1 preferentially induces spindle defects and cell death in transformed cells. Given that complete loss of SART1 is incompatible with normal development, our findings suggest that transient or partial inhibition of SART1 may provide a basis for selectively eliminating transformed cells while sparing normal cells.

3-Deoxy-4-sulfonamido-butein derivatives promote cell cycle arrest and apoptosis by inhibiting EGFR/JAK2/STAT3 signaling in A549 lung cancer cells.

Baicalein protects human keratinocytes against PM2.5-induced apoptosis by suppressing oxidative stress, endoplasmic reticulum stress, and ERK/JNK signaling.

Grape seed proanthocyanidin extract suppresses bladder cancer by dual blockade of IMPDH1/2-mediated purine and pyrimidine nucleotide biosynthesis.

Iron-vacancy-tailored sonosensitive catalysts amplify noninvasive tumor suppression by apoptosis/pyroptosis co-induction.

Gestational diabetes mellitus (GDM) is a common pregnancy complication associated with adverse maternal and fetal outcomes. Although the prevalence of GDM is high, the molecular mechanisms involved in GDM-related placental dysfunction remain poorly understood. This study aimed to investigate the roles of Forkhead box O1 (FoxO1) and fibroblast growth factor 12 (FGF12; a non-FGF receptor) in regulating trophoblast survival under GDM conditions. Placental tissue from women with GDM and matched non-GDM controls were collected to assess FGF12 expression. HTR8/SVneo trophoblast cells under high-glucose conditions were used to assess cellular functional assays, including proliferation, migration, and apoptosis, following FGF12 knockdown or overexpression. The level of FGF12 was significantly attenuated in placental tissues from GDM cases. Silencing FGF12 decreased trophoblast growth and migration, and increased apoptosis induced by high glucose, while FGF12 overexpression reversed these effects. Mechanistically, FoxO1 directly bound to the FGF12 promoter, downregulated its expression. In placental samples from GDM pregnancies, FoxO1 expression was negatively correlated with FGF12 levels. Furthermore, FoxO1 inhibited trophoblast proliferation and migration, while FGF12 overexpression partially rescued the inhibitory effects of FoxO1. These findings suggest that the FoxO1/FGF12 pathway may contribute to impaired trophoblast function in GDM. This study provides preliminary evidence for a regulatable molecular pathway involved in GDM-associated placental dysfunction; however, further validation in larger cohorts and physiologically relevant models is required before clinical applications can be applied.

Prostate cancer is the most prevalent malignancy among men and is driven by multiple factors, including androgen signaling and its receptor. Long non-coding RNAs, such as PVT1, play key roles in cancer, particularly by regulating gene expression. PVT1 is upregulated in several cancer types and has been shown to interact with the androgen receptor in prostate cells. This study investigates how PVT1 contributes to the prostate cancer phenotype under androgen stimulation. Knockdown of PVT1 was achieved using CRISPR-Cas13d in LNCaP prostate cancer cells subjected to androgen (R1881) or vehicle treatment. Cellular proliferation, invasion, and apoptosis rates were assessed, alongside RNA sequencing (RNA-seq) to analyze genome-wide transcriptomic changes. Six epigenetic marks-AR, EZH2, H3K4me1, H3K4me3, H3K27me3, and H3K27ac-were examined using CUT&RUN. PVT1 knockdown led to a significant reduction in cell proliferation and an increase in apoptosis signaling. Oncogenes such as MYC, AKT1, AKT2, cyclins CCNA2, CCNB1, CCNB2, CCNE1, CCNE2 and cyclin-dependent kinases CDK1 and CDK4, which were upregulated under androgen treatment, exhibited a significantly reduced expression following PVT1 knockdown, thereby modulating cancer-associated oncogenic pathways. Epigenetically, PVT1 knockdown markedly decreased the occupancy of transcriptionally activating epigenetic marks-H3K4me1, H3K4me3, and H3K27ac-on oncogenes, regardless of androgen presence. Analysis of enriched transcription factors associated with the altered genes revealed a regulatory network linked to prostate cancer pathogenesis. PVT1 drives a genome-wide epigenetic reprogramming in prostate cells, underscoring the role of PVT1 as a positive regulator of oncogenic pathways in prostate cancer and highlighting PVT1's potential as a therapeutic target.

The treatment of glioblastoma remains a major clinical challenge, largely due to intrinsic and acquired resistance to Temozolomide (TMZ). We aim to advance a novel therapeutic approach to overcome TMZ resistance in human glioblastoma by using the neuronal nitric oxide synthase inhibitor BA-101 as both a monotherapy and an adjuvant therapy. This approach leverages the additive anti-cancer activity of BA-101 to enhance the efficacy of TMZ and thereby improve treatment outcomes for glioblastoma patients. We used TMZ-resistant human glioblastoma LN-18 and LN-229 cells to study the therapeutic potential and additive anticancer activity of nNOS inhibitor BA-101 using invitro cancer functional assays, including cell proliferation, cell invasion, and migration assays, and biochemical assessment of biomarkers for nitrosative stress, and apoptosis using western blot analysis, flow cytometry and AnnexinV/PI staining. We further performed an invivo preclinical evaluationusing an LN-229 xenograft tumor model in SCID mice. Our findings demonstrate that BA-101 displays significant anti-cancer activity and sensitizes resistant glioblastoma cells to TMZ, reducing nitrosative stress, inhibiting clonogenic growth, invasion and migration, and promoting apoptotic cell death. It also demonstrates a significant decrease in tumor volume, suggesting that BA-101 exerts additive anti-tumor activity when used as an adjuvant to TMZ in SCID mice bearing LN 229 xenografts. Collectively, our findings strongly suggest that BA-101 has potential for further preclinical and translational development as an anticancer agent and a novel TMZ chemosensitizer for GBM therapy.