Anti-Cancer Agents in Medicinal Chemistry - Online First

The presence of severe hypoxic stress can drive tumor growth, angiogenesis, and metastatic characteristics via up-regulated hypoxia-inducible factor 1-alpha (HIF-1a). Hence, targeting HIF-1α is considered a promising strategy, as increased HIF-1α activity is a key factor in the aggressive phenotype of malignancies. In this study, we aimed to investigate the anti-cancer effects of several flavonoids, both single and in combination with PX-478, in breast cancer cell lines.

We tested the effects of luteolin and PX-478, both alone and in combination, on HIF-1a level in breast cancer cells under hypoxia using the cell viability assay. To determine the rationale for the cell growth inhibition induced by the luteolin+PX-478 combination, we conducted experiments to assess cell survival, apoptosis, cell cycle, invasion, and migration under both normoxic and hypoxic conditions. Furthermore, we evaluated the effect of this combination on DNA damage response under hypoxic stress via Comet assay and immunofluorescence staining.

Our findings revealed that the luteolin+PX-478 combination significantly suppressed the growth of MDA-MB-231 cells. In addition, we assessed time-dependent expression of HIF1a in MDA-MB-231 cells and observed that the combination of luteolin and PX-478 down-regulated the HIF-1a level. Finally, we found that the luteolin+PX-478 combination induced apoptosis and G2 cell cycle arrest and enhanced DNA damage response. This combination also sensitized breast cancer cells to ionizing radiation in hypoxic stress.

The findings suggested that targeting HIF-1α with a combination of luteolin and PX-478 may provide a synergistic approach to suppressing tumor growth and enhancing therapeutic response under hypoxic conditions. The observed effects on apoptosis, cell cycle arrest, and DNA damage response indicated that this combination could be a promising strategy for overcoming hypoxia-induced resistance in breast cancer therapy.

Collectively, our results suggested the combination of luteolin and PX-478 to enhance the anti-cancer effects of PX-478 in breast carcinoma cells by impeding the cell growth and inducing DNA damage response under hypoxia.

Lung cancer remains a leading cause of cancer-related deaths worldwide, with its incidence continuing to rise. Despite advancements in clinical treatments, their effectiveness is often restricted, emphasizing the need for novel therapeutic strategies. Natural products have long been explored for drug development, and among them, polysaccharides have gained significant attention due to their biocompatibility, biodegradability, and multiple biological functions.

A comprehensive review examined contemporary research on the anticancer properties of natural polysaccharides, focusing specifically on their effects in lung cancer. The analysis included studies investigating their influence on cancer cell growth, immune system modulation, and therapeutic outcomes. Evidence from laboratory (in vitro), animal (in vivo), and clinical studies was evaluated to provide a comprehensive overview of their potential role in lung cancer management.

Findings from recent studies indicate that polysaccharides can effectively inhibit the proliferation of lung cancer cells, thereby slowing tumor development. These compounds also appear to enhance immune responses by activating various immune cells and regulating cytokine production. Furthermore, polysaccharides have been shown to positively affect the gut microbiota, which may contribute to improved drug efficacy and a reduction in resistance to chemotherapy.

The evidence suggests that natural polysaccharides exert multifaceted effects in the context of lung cancer treatment. Their ability to directly suppress tumor growth, modulate the immune system, and interact with the gut microbiome positions them as promising adjuncts to existing therapies. However, the precise molecular mechanisms underlying these effects are not yet fully understood, and variability in study designs warrants cautious interpretation of the results.

Natural polysaccharides represent a promising complementary approach for lung cancer therapy, given their potential to inhibit tumor progression, enhance immune function, and improve the effectiveness of conventional drugs. Continued research is essential to fully elucidate their mechanisms of action and to translate these findings into effective clinical interventions.

VPS9 domain-containing 1 antisense RNA 1 (VPS9D1-AS1), also known as c-Myc-upregulated lncRNA (MYU) and FAK-interacting and stabilizing lncRNA (FAISL), is a novel long non-coding RNA (lncRNA) located at the human chromosome 16q24.3 locus. It has been reported to be highly expressed in various human cancers and associated with poor clinical pathological features and unfavorable prognosis in eight of the malignant tumors.

A comprehensive literature search was conducted using PubMed, Web of Science, and Google Scholar databases to identify relevant articles on “VPS9D1-AS1”, “MYU”, or “FAISL”. Only peer-reviewed publications were included, and articles related to oncology were specifically collected.

Mechanistically, VPS9D1-AS1 serves as a key regulator in four molecular models: signal, scaffold, guide, and decoy. These functions allow it to regulate the expression of target genes and activation of signaling pathways, thereby influencing the malignant phenotype of tumors.

The diverse molecular mechanisms of VPS9D1-AS1 highlight its significant role in the development and progression of various cancers. Its ability to act as a signal, scaffold, guide, and decoy suggests that it can influence multiple aspects of tumor biology, including proliferation, invasion, and metastasis.

VPS9D1-AS1 plays a significant role in the development and progression of various cancers through its diverse molecular mechanisms. Further research on VPS9D1-AS1 may provide valuable insights, which may facilitate the development of new diagnostic and therapeutic strategies for cancer.

Chemotherapy faces limitations such as toxicity and resistance, necessitating novel cancer treatments. Green-synthesized zinc oxide nanoparticles (ZnO-NPs) have attracted attention for their safety, biocompatibility, and therapeutic potential. This study investigates the anticancer efficacy of ZnO-NPs synthesized using the extracellular matrix of Aspergillus biplanus against colorectal cancer cell lines (HCT-116).

ZnO-NPs were synthesized extracellularly using A. biplanus fungal extract. The nanoparticles were characterized through UV-Vis spectrophotometry, showing an absorbance peak at 375 nm, and scanning electron microscopy (SEM), which determined their morphology and size. The anticancer activity was evaluated in vitro using HCT-116 cells. Reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) were assessed to understand the mechanism of cytotoxicity. In vivo studies were proposed for further validation.

The synthesized ZnO-NPs appeared pale white and exhibited a characteristic absorbance at 375 nm. SEM revealed spherical particles ranging from 35–150 nm. The ZnO-NPs showed strong anticancer activity with an IC50 value of 40.6 µg/mL. ROS levels increased significantly in treated cells, while the MMP decreased to 77.25% compared to 100% in controls.

ZnO-NPs exerted cytotoxic effects via ROS generation and mitochondrial dysfunction. These results underscore the nanoparticles’ ability to induce apoptosis in cancer cells through oxidative stress pathways.

Biogenically synthesized ZnO-NPs from A. biplanus show promise as eco-friendly anticancer agents. Further in vivo studies are recommended to confirm their therapeutic potential.

Timosaponin A-III (TAIII) is an effective anti-tumor ingredient extracted from the rhizomes of Anemarrhena asphodeloides. However, the effect of TAIII on prostate cancer cells (PCa) and its underlying mechanisms is rarely investigated. The current study aimed to investigate the anti-tumor effect and potential mechanisms of TAIII in PCa cells.

The effect of TAIII on the cell proliferation of PCa was evaluated by CCK-8 assay, colony formation assay, and EDU assay. Cell apoptosis and reactive oxygen species (ROS) production were evaluated by flow cytometry. The puncta of LC3 were detected by immunofluorescence analysis. The protein levels of apoptosis, autophagy, and AMPK/mTOR pathway were assessed by western blot. Finally, a PC3 xenograft nude mouse model was constructed to determine the effect of TAIII combined with chloroquine (CQ) in vivo.

Our data showed that TAIII inhibited the proliferation of PCa cells and induced ROS-dependent apoptosis. TAIII treatment dramatically promoted the formation of LC3-positive puncta, and increased the expression of LC3B-II and P62 protein. Moreover, the combination of TAIII with CQ significantly enhanced the pro-apoptosis effect of TAIII in PCa cells and the PC3 xenograft model. In addition, the activation of the AMPK/mTOR pathway and the induction of autophagy induced by TAIII were reversed by Compound C. Suppressing AMPK with Compound C enhanced the apoptosis induced by TAIII in PCa cells.

This study establishes TAIII as a potent anti-prostate-cancer agent that kills tumor cells via ROS-driven apoptosis while simultaneously triggering cytoprotective autophagy through the AMPK–mTOR axis. However, TAIII’s clinical potential awaits pharmacokinetic, bioavailability, and toxicity evaluation.

TAIII induced ROS-mediated cell apoptosis and promoted cytoprotective autophagy via the AMPK/mTOR pathway in PCa. These findings may provide a new strategy for combining TAIII with CQ together for PCa treatment.

Lung cancer progression involves complex interactions between metabolic pathways and the immune microenvironment. The role of serotonin, a tryptophan-derived metabolite, in immune responses to lung tumors remains unclear.

An orthotopic lung cancer model was established by intravenously injecting KP (Kras^G12D/p53^-/-) cells into C57BL/6 mice. Metabolomic and flux analyses were conducted on tumor versus normal lung tissues. Serotonin was administered to tumor-bearing mice, followed by immunofluorescence and flow cytometry to assess immune responses. Human lung cancer datasets were analyzed to validate clinical relevance.

Tumor tissues exhibited a significant decrease in serotonin levels. Although tryptophan, serotonin, and kynurenine levels were decreased overall, flux analysis revealed a metabolic shift favoring kynurenine synthesis, with a ~10-fold increase in the kynurenine-to-serotonin ratio. Serotonin supplementation significantly prolonged survival and enhanced dendritic cell and CD8⁺ T cell infiltration and activation in tumors. Analysis of public datasets showed that serotonin expression positively correlated with CD8⁺ T cell activation signatures and patient prognosis.

By revealing serotonin as a potential biomarker and therapeutic target, this study paves new avenues for improving lung cancer treatment strategies through modulation of the immune microenvironment. Moreover, the precise receptor-mediated mechanisms underlying serotonin's immunomodulatory effects remain to be clarified, and translational validation in human tissues is warranted to strengthen clinical relevance.

Serotonin deficiency in the tumor microenvironment of the lung suppresses antitumor immunity. Its restoration reverses immune dysfunction and limits tumor progression. These findings identify serotonin as a potential metabolic regulator and immunotherapeutic target in lung cancer.

This study aims to identify the key genes and pathways associated with sotorasib resistance in Non-Small Cell Lung Cancer (NSCLC) using bioinformatics analyses and experimental validation, with a focus on uncovering the potential mechanisms underlying resistance.

We compared gene expression profiles between sotorasib-resistant (SR) and non-resistant NSCLC cell lines using the GSE229070 dataset and between NSCLC tissues and adjacent normal tissues using the GSE18842 dataset. Differentially expressed genes (DEGs) were identified and intersected across datasets using the Venn diagram package. Functional enrichment analysis was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The transcriptional activity and prognostic impact of key genes were evaluated using the UALCAN portal and Kaplan-Meier Plotter, respectively. The correlation between gene expression and immune cell infiltration was analyzed using the TIMER database, and co-expressed genes were explored using LinkedOmics. qRT-PCR and Western blot were used to validate the expression of AREG in parental and SR cell lines.

We identified 33 overlapping DEGs, including TENM2, COL12A1, COL5A2, and LRRC15 (upregulated) and AREG (downregulated). AREG expression was significantly lower in NSCLC patients and associated with worse survival outcomes. AREG expression was also correlated with the levels of immune cell infiltration. Functional enrichment analysis revealed that AREG was associated with pathways including the NOD-like receptor signaling pathway, focal adhesion, DNA replication, and homologous recombination. Experimental validation confirmed that AREG mRNA and protein levels were significantly reduced in HCC78-SR cells compared to parental HCC78 cells.

The downregulation of AREG is closely associated with sotorasib resistance in NSCLC, potentially contributing to resistance through alterations in signaling pathways and the tumor immune microenvironment. This finding aligns with previous studies on AREG's role in drug resistance, highlighting its potential as a therapeutic target. However, limitations include reliance on publicly available datasets and the need for further validation in clinical cohorts.

The study identifies AREG as a key gene associated with sotorasib resistance in NSCLC, suggesting its potential as a biomarker and therapeutic target. Further research is needed to elucidate the mechanisms underlying AREG's role in resistance and to explore its clinical significance.