Anti-Cancer Agents in Medicinal Chemistry - Online First

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.

Laryngeal cancer is a common malignant tumor of the head and neck worldwide. This study aimed to identify potential risk genes, with a particular focus on GPR65, and to investigate its functional mechanism in pathogenesis of laryngeal cancer.

Comprehensive analyses, including scRNA-seq analysis, genome-wide association study (GWAS), eQTL, and TCGA data, were conducted to identify risk genes for laryngeal cancer and characterize the function of these risk genes. Next, qRT-PCR, immunohistochemistry, cell proliferation, cell migration, and invasion assays were employed to verify the expression of GPR65 and its function in laryngeal squamous cell carcinoma (LSCC) in vitro.

Single-cell analysis screened 416 highly expressed genes in CD8+ central memory T cells (CD8_CM). Mendelian randomization (MR) analysis identified GPR65 as a crucial gene in the development of laryngeal cancer. GPR65 expression was significantly elevated in the tumor tissues compared to normal tissues, with particularly high levels observed in stage IV HNSCC. In vitro, LSCC cell lines (TU686 and Hep-2) exhibited marked upregulation of GPR65 relative to normal epithelial cells, and siRNA-mediated silencing of GPR65 suppressed the proliferation, migration, and invasion of LSCC cells. Furthermore, GPR65 expression showed a positive correlation with immune cell infiltration, particularly CD8+ T cells and M1 macrophages.

This study identified GPR65 as a potential risk gene for laryngeal cancer through single-cell transcriptomics and MR analyses and provided novel evidence of its involvement in the development of the cancer.

The present findings showed that highly expressed GPR65 was a tumor-promoting gene in laryngeal cancer, showing its clinical value as a potential therapeutic target.

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.

Rosmarinic acid (RA) is a phenolic acid known for its important biological activities. Although it has been shown to inhibit various cancer cell types, its effects on the suppression and induction of apoptosis in neuroblastoma cells remain unclear. In this study, the antiproliferation and apoptosis-inducing effects of various concentrations of rosmarinic acid on neuroblastoma cells (SH-SY5Y) were investigated. Additionally, molecular docking analysis was conducted to examine the interaction between rosmarinic acid and the antiapoptotic protein BCL2.

SH-SY5Y cells were treated with rosmarinic acid at concentrations of 50, 100, 150, and 200 µg/ml for 24 hours. The percentages of apoptotic and necrotic cells in cultures treated with the lowest and highest concentrations were assessed using the Annexin V/PI staining method. Furthermore, the interaction between rosmarinic acid and BCL2 protein was analyzed using molecular docking techniques.

The viability of rosmarinic acid-treated SH-SY5Y cells decreased. In SH-SY5Y cells, the percentage of late apoptotic cells increased to 40%. Molecular docking results showed that the benzene ring of rosmarinic acid formed pi-alkyl interactions with PHE71 and van der Waals interactions with SER64, ALA72, SER75, and VAL115 of BCL2. The lowest binding energy was calculated as -7.2 kcal/mol.

RA demonstrated a suppressive effect on SH-SY5Y cells by targeting the antiapoptotic protein BCL2, suggesting a potential mechanism of action through the induction of apoptosis.

RA inhibited neuroblastoma SH-SY5Y cell proliferation and induced apoptotic cell death. It inhibited the proliferation of neuroblastoma SH-SY5Y cells and promoted apoptotic cell death, potentially through interaction with the BCL2 protein.

PTEN (Phosphatase and tensin homolog) is a valuable regulator of the PI3K-AKT and mTOR pathways and is frequently mutated in cancer-like glioblastoma. The WWPI HECT domain has a group of enzymes called E3 ligases that ubiquitinate and inactivate PTEN by binding to it, which ultimately inhibits its lipid phosphatase function and promotes nuclear delocalization. This investigation seeks to restore the PTEN tumor suppressive activity by inhibiting the WWPI HECT domain in-silico.

We virtually screened a library of ~960 compounds in the active pocket of the human WWPI HECT domain, and fifteen compounds were chosen based on their favorable binding affinities and highly negative docking scores.

Among those hits, five compounds, C5, C6, C8, C9 and C11, properly fit the standard with favorable pharmacokinetic and drug-like quality. Their capacity to suppress cell propagation was evaluated in the U87 glioma cell line. The compounds (C5, C6, C8, C9 and C11) exhibited significant anti-proliferative capability with IC50 values of 6.98 ± 0.14 µM, 14.58 ± 1.49 µM, 11.12 ± 0.73 µM, 13.85 ± 1.63 µM and 18 ± 1.23 µM, respectively.

Strong inhibitory action against glioma cells was shown by the discovered compounds, especially C5 and C8, suggesting that they may be able to restore PTEN tumor suppressive capabilities. A potential therapeutic intervention mechanism for glioblastoma is suggested by their interaction with the WWPI HECT domain.

This study has discovered novel inhibitors against the WWPI HECT domain, and a treatment option for glioblastoma.

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.