Anti-Cancer Agents in Medicinal Chemistry - Online First

Breast cancer remains a leading cause of cancer-related mortality in women, primarily due to Breast Cancer Stem Cells (BCSCs), which contribute to tumor progression, metastasis, and resistance to conventional therapies. Vitex negundo Linn. (VN), a medicinal plant abundant in polyphenolic flavonoids such as luteolin (LT), has previously demonstrated anticancer potential. This study investigates the active metabolite profiling of VN targeting BCSCs and evaluates LT’s therapeutic potential through in vitro and in silico approaches.

An integrated network pharmacology and computational approach identified VN metabolites targeting BCSCs, including CDK1, cyclin B1/B2, TOP1, GSK-3β, and PARP1. Mutational analysis in MCF-7 cells followed by luteolin (LT) treatment assessed its impact on stemness, gene expression, ROS generation, cell cycle, and apoptosis. Molecular docking and dynamics confirmed LT’s strong binding to CDK1/Cyclin B.

LT significantly reduced the properties of BCSCs by inhibiting the CDK1/Cyclin B complex and downregulating associated genes. It induced ROS-mediated apoptosis and altered cell cycle distribution, notably increasing G1 and S phase populations. Molecular modeling confirmed strong binding of LT to CDK1/Cyclin B, suggesting disruption of cell cycle regulation and self-renewal.

LT binds strongly to CDK1 and Cyclin B proteins, suppressing their activity in MCF-7 cells. This disrupts gene expression linked to BCSC self-renewal, induces apoptosis, and causes cell cycle arrest. LT targeting CDK1/Cyclin B complexes offers promising therapeutic potential for future clinical development against BCSCs.

LT from VN shows promise as a therapeutic agent targeting CDK1/Cyclin B in ER+ breast cancer stem cells, supporting its potential for clinical development.

Radiotherapy (RT) is a standard cancer treatment that may be associated with problems such as ineffectiveness and side effects. This study investigated ginsenosides' radiosensitizing and radioprotective properties and their metabolites during RT.

This study searched databases including PubMed/MEDLINE, Scopus, Embase, and Cochrane Library for articles before January 28, 2025. After specifying the inclusion and exclusion criteria, relevant articles were imported into EndNote software and screened. Then, the data were recorded in tables and analyzed.

After the screening process, 28 articles were included. Ginsenosides exhibited radioprotective effects in normal tissues by reducing oxidative stress, preserving mitochondrial integrity, enhancing DNA repair, modulating inflammatory pathways, and supporting hematopoiesis. Key compounds such as Rg1, Rg3, and Rh2 promoted tissue regeneration and protected against radiation-induced organ damage. In tumour cells, ginsenosides enhance radiosensitivity by increasing reactive oxygen species (ROS), disrupting mitochondrial function, inducing DNA damage and cell cycle arrest, and promoting apoptosis. They also inhibited tumour progression via nuclear factor kappa B (NF-κB) suppression and immune activation, reducing angiogenesis and metastasis. These dual actions suggest their potential to improve radiotherapy outcomes.

Ginsenosides revealed dual roles as radioprotective and radiosensitizing agents, highlighting their potential in improving RT outcomes. However, the limited clinical data and lack of ginseng extract studies indicate the need for future clinical studies to establish optimal dosing, safety, and relevance for humans.

The findings of both in vivo and in vitro studies indicated that ginsenosides enhance RT and provide protective effects against the harmful impacts of ionizing radiation.

Hypopharyngeal Squamous Cell Carcinoma (HSCC) is associated with a poor prognosis due to challenges in early detection, early metastasis, and limited treatment options.

This study aims to investigate the effect of metformin on HSCC and identify potential prognostic factors associated with this carcinoma.

The effects of metformin in HSCC cells were tested by functional assays in vitro. A xenograft tumor model was established, which was further examined by H&E staining, immunohistochemistry, and transmission electron microscopy (TEM). RNA sequencing analysis was employed to investigate the effects of metformin on gene expression and associated pathways. Bioinformatic analysis was further conducted to elucidate potential mechanisms and their correlation with gene expression, the tumor immune microenvironment, and survival prognosis. Finally, we further assessed the effect on FaDu cells by knocking down lncAROD using siRNAs.

The results demonstrated that metformin significantly reduced cell viability and migration, while promoting apoptosis and inducing cell cycle arrest in FaDu cells. WB analysis revealed that metformin inhibits the development of FaDu cells, possibly through the EMT pathway. In vivo studies indicate that metformin effectively inhibits tumor growth, promotes apoptosis, and autophagy. RNA-seq analysis revealed that metformin led to the upregulation of 1,697 genes and the downregulation of 858 genes, particularly highlighting a significant reduction in lncAROD, which were subsequently verified by qRT-PCR. Bioinformatic analysis demonstrated that lncAROD is highly expressed, with patients exhibiting higher levels of lncAROD showing poorer prognoses. Knockdown of lncAROD can reduce the proliferation, migration, and invasion of FaDu cells.

This finding presents a novel approach to the clinical management of HSCC, indicating that metformin influences various processes related to the growth and progression of HSCC. Specifically, it reduces lncAROD expression and inhibits tumor progression, suggesting that lncAROD may serve as a valuable biomarker for evaluating the prognosis of HSCC.

Chemotherapy-induced gastrointestinal reactions are common in non-small cell lung cancer (NSCLC) patients undergoing carboplatin-based chemotherapy. Jianpi Yiwei granules (JPYW), a traditional Chinese medicine (TCM) formula, can alleviate these symptoms.

This multi-center, randomized, double-blind, placebo-controlled trial enrolled 136 NSCLC patients scheduled for carboplatin-based chemotherapy. Participants were randomly assigned to the treatment group (JPYW with standard antiemetic drugs) and the control group (placebo with standard antiemetic drugs). The complete control rate of nausea and vomiting was assessed using the Visual Analog Scale (VAS) and patient diaries. Control of anorexia, bloating, constipation, and quality of life was measured using the Functional Living Index-Emesis scale and the Brief Fatigue Inventory (BFI).

The primary objective of this study was to assess the efficacy of JPYW in alleviating non-vomiting digestive symptoms, such as nausea and anorexia, in NSCLC patients receiving carboplatin-based chemotherapy. The secondary objective was to evaluate its effect on improving bloating, constipation, quality of life, and safety.

Previous studies have shown that Chinese herbs, such as ginger, are effective in treating chemotherapy-induced nausea and vomiting (CINV). JPYW, a multi-component TCM formula, contains active compounds from Codonopsis pilosula and Atractylodes macrocephala. JPYW exerts anti-inflammatory and prokinetic effects that can synergistically regulate gastrointestinal functions. Preliminary observations confirmed the safety of JPYW combined with standard chemotherapy.

The current findings contribute to the treatment of adverse reactions to tumor chemotherapy and are expected to improve the quality of life for chemotherapy patients.

Esophageal cancer often develops insidiously, with most cases diagnosed at an advanced stage. Currently, the pathogenesis of esophageal cancer remains unclear, treatment outcomes are poor, and the five-year survival rate is low. To tackle the significant clinical challenges of difficult diagnosis and unfavorable prognosis, it is crucial to actively investigate the disease's pathogenesis. This study explored the involvement of telomere shelterin protein TPP1 in the pathogenesis of esophageal cancer and identified potential therapeutic agents for its treatment.

The expression level of TPP1 protein in 54 pairs of esophageal cancer tissues and paired adjacent tissues was detected via immunohistochemistry. The impact of TPP1 silencing and Elbasvir administration on the growth of KYSE150 and TE1 esophageal cancer cell lines was assessed utilizing Cell Counting Kit-8 and colony formation assays. Cell migration was assessed through Transwell and scratch assays. Fluorescence microscopy was employed to observe autophagosome formation, while flow cytometry measured the fluorescence intensity of autophagy markers LC3 and P62 in TPP1-silenced KYSE150 and TE1 cells. Western blotting was utilized to examine the alterations in TPP1, the AKT-mTOR signaling pathway, autophagy-related proteins, and other associated proteins.

TPP1 levels were notably elevated in esophageal squamous cell carcinoma tissues relative to adjacent normal tissues. Suppression of TPP1 substantially reduced the growth and movement of esophageal cancer cells in vitro, while triggering autophagy via the AKT-mTOR signaling pathway, highlighting TPP1’s cancer-promoting function in esophageal cancer.

Elbasvir effectively suppressed the growth and spread of KYSE150 and TE1 cell lines in vitro, downregulating TPP1 protein expression in relation to time and dosage. Additional investigations revealed that Elbasvir also inhibited the AKT-mTOR signaling axis and induced autophagy by targeting TPP1. Notably, rescue experiments demonstrated that 3-MA could reverse the inhibitory effects on proliferation, migration, and autophagy induced by TPP1 silencing or Elbasvir treatment in KYSE150 and TE1 cells.

TPP1 emerges as a compelling diagnostic indicator and a potential treatment focus in esophageal cancer, with Elbasvir offering promise as a novel therapeutic agent.

The emergence of immune checkpoint inhibitors has revolutionized the treatment of cancer. Among these, the programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis remains a critical target. However, resistance to current biologics necessitates the development of novel Small-Molecule Inhibitors (SMIs) with distinct mechanisms and improved pharmacological profiles. This review provides a comprehensive analysis of recent progress in PD-L1-targeting SMIs, including original compounds from our laboratory.

We conducted a structured literature review using electronic databases such as PubMed, Scopus, and Web of Science. Articles published between 2015 and 2025 were included based on relevance to small-molecule PD-L1 inhibitors in cancer immunotherapy. Key data were extracted and synthesized regarding molecular design strategies, mechanisms of action, pharmacokinetics, and therapeutic efficacy. Compounds synthesized in our laboratory (Compounds 5–10 [A56]) were evaluated using in vitro assays, including PD-L1/PD-1 binding inhibition, cancer cell viability assays, and gene expression profiling.

Recent SMIs exhibit diverse functional profiles: direct blockade of PD-1/PD-L1 interaction, intracellular PD-L1 modulation, and transcriptional downregulation. Notably, Compound 7 demonstrated significant suppression of PD-L1 mRNA expression, while Compounds 9 and 10 (A56) achieved nanomolar-level binding affinity. These findings reflect innovative approaches to overcoming immune resistance and enhancing antitumor responses.

Our findings underscore a trend toward multifunctional PD-L1-targeting SMIs that operate through both extracellular and intracellular mechanisms. Compounds from our laboratory represent potential leads for further optimization and clinical translation. However, challenges remain regarding oral bioavailability, metabolic stability, and immune-related adverse events.

Small-molecule PD-L1 inhibitors offer a promising avenue for expanding cancer immunotherapy. Our review highlights key advances and introduces novel small-molecule PD-L1 inhibitors with strong potential for future development, particularly in combination regimens.

Diffuse large B-cell lymphoma (DLBCL) is one of the most prevalent hematological malignancies with high mortality. G1 to S phase transition 1 (GSPT1), a key translation termination factor involved in protein synthesis, has been implicated in tumor progression. This study aimed to investigate the effectiveness and underlying mechanisms of the GSPT1 degrader SJ6986 in DLBCL.

The TCGA and GTEx datasets were utilized to assess the expression of GSPT1 in DLBCL. The viability and proliferation of DLBCL cells were detected using the Cell Counting Kit-8 (CCK-8) assay. Cell apoptosis was detected via flow cytometry. The expression of GSPT1 was evaluated using qRT-PCR and Western blot. Xenograft mouse models were employed to explore the in vivo therapeutic potential of SJ6986. RNA sequencing was used to explore the potential mechanism of SJ6986 in DLBCL.

This study first identified that GSPT1 is highly expressed in DLBCL and demonstrated that its genetic knockdown significantly suppressed the activity of DLBCL cells. Furthermore, it was found that SJ6986 effectively reduced the proliferation of DLBCL cells, induced cell apoptosis, and inhibited tumor growth in vivo without significant toxicity. Mechanistically, RNA sequencing analysis showed that the endoplasmic reticulum (ER) stress was significantly triggered following SJ6986 treatment, and SJ6986 was found to activate the ER stress-related apoptosis in DLBCL cells.

Our findings suggested that SJ6986 exerts its anti-tumor effects in DLBCL and activates the ER stress-related apoptotic signaling. These results supported SJ6986 as a viable anticancer drug for treating DLBCL. Future studies should further investigate its mechanism and evaluate its clinical application value.

This study validated the efficacy and safety of SJ6986 in treating DLBCL and discovered its role in inducing ER stress and subsequent apoptosis, offering a promising therapeutic option for DLBCL patients.

Prostate cancer (PRAD) remains a leading malignancy with limited prognostic biomarkers and therapeutic targets. PRR22, a proline-rich protein-coding gene, has a role in PRAD that remains undefined. This study is the first to systematically investigate the clinical relevance and mechanistic implications of PRR22 in PRAD.

PRR22 expression was analyzed in TCGA-PRAD (n = 501), GSE55945, and the Human Protein Atlas datasets. Prognostic value was assessed via Kaplan-Meier and multivariate Cox analyses. Mechanistic insights were derived from GSEA, immune infiltration profiling, MSI/mRNA-si correlations, and drug sensitivity analysis. Experimental validation was performed via qRT-PCR in PRAD cell lines.

PRR22 was significantly upregulated in PRAD tissues compared to normal tissues (p < 0.001) and independently predicted shorter progression-free survival (HR = 1.82, p = 0.009). Novel associations were identified between PRR22 and TGF-β signaling, immune evasion (e.g., LAG3 upregulation), microsatellite instability (MSI), and stemness (mRNA-si). High PRR22 correlated with resistance to multiple drugs (e.g., bicalutamide, vorinostat).

PRR22 overexpression in PRAD is linked to poor prognosis and immune regulation, suggesting its potential as a prognostic biomarker and therapeutic target. Future research should focus on clinical validation and on exploring the molecular mechanisms underlying PRR22's role in PRAD.

PRR22 is a novel, independent prognostic biomarker and actionable therapeutic target in PRAD, linking tumor aggressiveness to immune microenvironment remodeling and drug resistance. These findings establish PRR22 as a candidate for clinical implementation in risk stratification and targeted therapy.