Anti-Cancer Agents in Medicinal Chemistry - Online First

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.

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.

Copper complexes, as endogenous metals, have potential in cancer therapy, addressing issues associated with cisplatin. Since cisplatin uses Copper Transporter 1 (CTR1) for cellular entry, copper complexes may utilize this pathway to enhance transport efficiency.

The Cu/Na dipicolinic acid complex was synthesized to assess its cytotoxicity, induction of apoptosis, drug resistance, and inflammation in cancerous and normal lung cells. The effects of oxidative stress on erythrocytes were also examined.

Cytotoxicity tests (MTT and SRB) showed superior inhibitory effects on A549 lung cancer cells compared to cisplatin, with no toxicity observed in MRC-5 normal lung fibroblast cells. Real-time PCR revealed increased caspase-3 expression (extrinsic apoptosis) for the complex compared to cisplatin, possibly due to CTR1-mediated entry. The complex did not induce drug resistance, as shown by AKT1 expression, and reduced TNF-α expression, preventing inflammation in normal cells. In contrast to cisplatin, the complex caused minimal oxidative stress in erythrocytes.

It can be concluded that the Cu/Na dipicolinic acid complex may be easily transported by CTR1 to malignant tumors, particularly lung cancer. This complex has the ability to inhibit cancer cell growth and induce apoptosis in lung cancer cells. Therefore, copper complexes show promise as potential therapeutic options for treating this type of cancer.

The copper/sodium complex demonstrates enhanced therapeutic efficacy in lung cancer cells, requiring lower doses than cisplatin, while being safer for normal cells and erythrocytes.

Microbial metabolites represent a valuable source of bioactive compounds with promising anticancer properties. However, conventional drug discovery approaches are time-intensive and resource-demanding.

Recent developments in artificial intelligence (AI), machine learning (ML), molecular docking, and quantitative structure-activity relationship (QSAR) modeling have been examined for their role in the identification and optimization of microbial metabolites.

AI-driven approaches have significantly enhanced compound screening and prediction of therapeutic efficacy. Nanocarrier-based drug delivery systems have improved the bioavailability, specificity, and stability of microbial metabolites while minimizing systemic toxicity. Despite these advancements, challenges remain in clinical translation due to the lack of in vivo validation and comprehensive pharmacokinetic data.

This review highlights the integration of advanced computational tools and nanotechnology in accelerating the discovery and delivery of microbial-derived anticancer agents.

Future directions should focus on integrating AI with synthetic biology to engineer microbial strains capable of producing enhanced bioactive compounds. Additionally, leveraging nanotechnology could refine targeted delivery mechanisms. A deeper understanding of molecular pathways and drug resistance mechanisms is essential to support the development of combination therapies. Overall, microbial-derived compounds hold substantial potential in advancing precision oncology.

Hepatocellular carcinoma (HCC) ranks among the leading causes of cancer-related deaths on a global scale. This study aimed to evaluate the effects of euxanthone on the proliferation of HCC cell lines and elucidate the underlying molecular mechanisms.

HCC cell lines (HepG2, Huh-7, SNU-398, SK-HEP-1, Hep3B) and the normal liver cell line THLE-2 were cultured and treated with euxanthone at concentrations between 0 and 100 µM. Cell viability was evaluated using the MTT assay, while phase contrast microscopy and cell cycle analysis were performed to evaluate morphological changes and cell cycle distribution. qRT-PCR was utilized to measure miRNA and mRNA expression levels, while a dual luciferase reporter assay validated the interaction between miR-199a-5p and E2F3.

Euxanthone significantly (P < 0.05) inhibited cell proliferation in all HCC cell lines, with IC50 values between 6.25 and 25 µM. HepG2 cells exhibited pronounced sensitivity, with an IC50 of 6.25 µM. Euxanthone induced a G1 phase arrest, characterized by decreased expression of Cyclin D1 and E, and increased levels of p21. Additionally, it upregulated miR-199a-5p, which was identified as a mediator of the antiproliferative effects by targeting E2F3. Euxanthone treatment also significantly (P < 0.05) inhibited HepG2 cell migration in a wound healing assay.

The findings demonstrate that euxanthone exerts its anticancer activity in HCC cells by modulating the miR-199a-5p/E2F3 axis, leading to G1 arrest and inhibition of migration. These results align with prior studies on natural compounds as modulators of oncogenic signaling pathways and highlight miR-199a-5p as a crucial mediator for anticancer effects of euxanthone. The low toxicity toward normal liver cells further emphasizes its therapeutic potential.

Taken together, euxanthone exerts antiproliferative effects on HCC cells via the miR-199a-5p–E2F3 axis and inhibits cell migration. These findings support its potential as a therapeutic agent for HCC, highlighting the need for further investigation into its clinical applications.

Ursolic acid (UA) exhibits antitumor activity; however, its effects and mechanisms on triple-negative breast cancer (TNBC) cells are not well understood. The present study aimed to explore the anti-TNBC mechanisms of UA by network pharmacology and experimental validation.

TNBC cell lines MDA-MB-231 and BT-549 cells were treated with UA. A CCK-8 assay was performed to detect cell growth, while flow cytometry assessed cell cycle arrest and apoptosis. The underlying mechanism and potential targets of UA for TNBC treatment were investigated by network pharmacology, including PharmMapper database, GO, KEGG enrichment, and PPI analysis. The protein expressions and phosphorylation levels of FGFR1, AKT, and ERK were measured by western blot. Pull-down assay, cellular thermal shift assay (CETSA), and molecular docking were used to analyze the interaction between UA and FGFR1. Xenograft models were established to examine the effect of UA on TNBC tumor growth.

UA effectively reduced cell viability, induced apoptosis, and arrested cell cycle in TNBC cells. Moreover, UA significantly regulated the expression of Bcl-2 and Bax to induce apoptosis. The results of network pharmacology and western blot suggested that UA reduced FGFR1/AKT/ERK pathway. Furthermore, pull-down, CETSA, and molecular docking results revealed that UA directly bound to FGFR1. In the xenograft model, UA inhibited the growth by suppressing FGFR1.

In this study, we employed network pharmacology and experimental approaches to elucidate the mechanism of UA on TNBC. The results demonstrated that UA targeted FGFR1 to inhibit TNBC via mediating FGFR1/AKT/ERK pathway.

Our findings demonstrate that UA inhibits the FGFR1/AKT/ERK pathway by directly targeting FGFR1, thereby suppressing TNBC progression and supporting its potential as a therapeutic agent for TNBC treatment.

Benzochromenes are heterocyclic compounds of growing interest in medicinal chemistry due to their diverse biological activities, including antioxidant, anticancer, and antimicrobial properties.

A one-pot, three-component synthesis was employed to prepare benzochromene derivatives (4a–f) using 2-naphthol or its derivatives, active methylene compounds, and 2-methoxybenzaldehyde in ethanol with piperidine as a catalyst. The compounds were evaluated for their anticancer activity against MCF-7, HepG-2, and HCT-116 cell lines, as well as for their antimicrobial activity through molecular docking studies targeting cancer-related and microbial proteins.

All synthesized compounds were obtained in moderate to good yields. Compounds 4c, 4e, and 4f demonstrated superior biological activity compared to standard drugs Doxorubicin and Augmentin. Docking studies revealed strong binding affinities to key targets, including the TGF-βI receptor and the choline-binding domain.

The hydroxyl group at position 9 in compounds 4c and 4f likely contributed to enhanced antimicrobial activity, while the bromo group in 4e correlated with significant anticancer effects. These findings suggest meaningful structure–activity relationships and validate the design strategy.

The synthesized benzochromene derivatives exhibit promising anticancer and antimicrobial activities. Supported by molecular docking, these findings lay the groundwork for further pharmacological and in vivo evaluations of this scaffold.

Aromatase inhibition is one of the most effective strategy for the treatment of ER+ breast cancer, which accounts for about 70% of breast cancer cases. Indole-based aromatase inhibitors have altered the dynamics of the search for anti-breast cancer drugs with efficacy in nanomolar concentrations. In the present study, we have integrated pharmacophore mapping with Gaussian-based 3D-QSAR analysis to map the essential pharmacophoric features of indole-based aromatase inhibitors, aiming to optimize lead molecules.

Pharmacophore mapping and Gaussian-based 3D-QSAR were integrated to identify the steric and electrostatic features essential for aromatase inhibitory activity.

A Gaussian-based 3D-QSAR model with an r² value of 0.7621 and stability of 0.817 was generated to determine the nature of substitutions essential for optimal biological activity. Pharmacophore mapping results indicated that H-bond Donor (D), a Hydrophobic (H) feature, and three aromatic rings (R) are essential for potent inhibitory activity.

In order to identify important structural characteristics of indole-based aromatase inhibitors, the current study successfully integrated pharmacophore mapping investigations with 3D-QSAR. The designed molecule S1 demonstrated activity comparable to letrozole, with a predicted pIC50 value of 9.332 nM.

The designed compound S1 demonstrated a predicted IC50 value of 9.332 nM, comparable to the most active compound 15 and the standard reference Letrozole. The developed models may be utilized by medicinal chemists for the optimization of new indole-based aromatase inhibitors for the effective treatment of ER+ breast cancer.

Breast cancer develops in breast tissues, in ducts and lobules. It affects both genders, though it is uncommon in men. Hematological variations are important considerations and deficiencies in metals can negatively impact human health. Cadmium is highly toxic and plays role in breast cancer progression. This study was designed for hematological variations and cadmium induced toxicity in mice and humans causing breast cancer.

Mice, obtained from local supplier, housed at university laboratory for 11 weeks, exposed to cadmium. Following dissection, blood and organs were harvested for examination. Histological analysis of liver and mammary gland tissues was conducted.

Affected mice had higher Hb, RBC, HCT, MCV, and MCH, while humans showed lower Hb, HCT, and MCV but similar RBC and MCH. Other blood values also show changes. Histopathology revealed changes in mammary glands (higher cadmium led to increased fat deposition, degeneration of alveolar epithelial cells, and a reduction in alveolar milk lumen size, indicating compromised glandular function) and Liver damage (vacuolation, lipid accumulation, fibrosis, and collagen deposition, was noticeable with prolonged cadmium). These changes causes liver fibrosis and impaired mammary gland function.

The cadmium exposure induces distinct hematological alterations and severe tissues damage, reflecting species-specific responses. The observed liver fibrosis and mammary gland dysfunction emphasize cadmium’s potential to compromise critical organ functions over time.

Significant effects of cadmium exposure in mice were observed. Histological damage was seen in mammary glands and liver. Further research on protective measures and dose-response relationships for cadmium exposure is needed.

Current research focuses on identifying and analyzing bioactive metabolites with significant therapeutic properties derived from Punic granatum L. (Pomegranate) leaves. Methods: The biological potential of these metabolites was evaluated through anticancer activity. In contrast, LC-QTOF-MS and GC-QTOF-MS methods were used to profile the metabolites. In silico molecular docking was performed using various online and offline tools to validate the active metabolites.

PAC exhibited significant anticancer activity. The identified metabolites were screened, and 40 compounds from different categories were chosen for further in silico interaction studies.

The molecular docking analysis discovered lead molecules that exhibited promising binding energy scores, efficiency, and stable modulation with specific protein domains. However, clinical trials are required for the applications of the lead molecules in the design of anticancer drugs.

The findings from both in vitro and in silico analyses support the notion that the P. granatum Acetone Extract (PAC) is an excellent source of potential metabolites with therapeutic properties. According to the findings, this research enhances the treatment of human breast cancer and validates several plant traditions for their numerous benefits.

Cancer metastasis and associated thrombosis are significant contributors to cancer-related mortality, necessitating therapeutic strategies that simultaneously address both issues. This study aimed to evaluate the dual anti-metastatic and anti-hypercoagulability properties of dHG-5, a low-molecular-weight fucosylated glycosaminoglycan derived from the sea cucumber Holothuria fuscopunctata.

The heparanase-inhibitory and anticoagulant effects of dHG-5 were assessed in vitro using biochemical assays. The impact of dHG-5 on 4T1 cell migration and invasion was evaluated using Transwell assays. The anti-metastatic and anti-hypercoagulability efficacy of dHG-5 was further tested in a 4T1 mammary carcinoma mouse model, with enoxaparin (LMWH) used as a control.

dHG-5 exhibited potent heparanase inhibition (IC50 = 91.0 nM) and significantly reduced 4T1 cell migration and invasion at 4.0 µmol/L. In vivo, dHG-5 reduced lung metastasis without affecting tumor growth or proliferation. At a dose of 20 mg/kg, dHG-5 prolonged activated partial thromboplastin time (APTT) from 23.5 ± 1.85 s to 30.4 ± 3.36 s, effectively reversing hypercoagulability in tumor-bearing mice. Compared to low-molecular-weight heparin, dHG-5 selectively prolonged APTT with negligible effects on prothrombin time and thrombin time.

The findings highlighted the dual-action mechanism of dHG-5, namely inhibiting heparanase and selectively targeting the intrinsic coagulation pathway. This selective action minimized bleeding risk, a common issue with traditional anticoagulants. However, this study focused on a single cancer type and the use of a mouse model, which may not fully represent human pathophysiology. We would explore dHG-5's effects across different cancer types and investigate its potential synergistic effects with existing cancer therapies in the future.

dHG-5 suppressed metastasis and hypercoagulability through heparanase inhibition and selective action on the intrinsic coagulation pathway. These findings highlight dHG-5 as a promising dual-action therapeutic candidate for managing metastasis and cancer-associated thrombosis, offering a safer alternative to traditional anticoagulants.

Cancer progression is increasingly understood to be influenced by neural mechanisms, including neurotransmitter signaling, neurotrophic factor activity, neuroinflammation, and neurogenic inflammation. These neurobiological interactions contribute to tumor proliferation, angiogenesis, and metastasis. Kinase inhibitors, a class of targeted therapies that block dysregulated kinase activity, have demonstrated promise not only in direct tumor suppression but also in modulating neural pathways associated with cancer progression.

This review examines the role of kinase inhibitors in modulating cancer-associated neural mechanisms. A comprehensive literature search was conducted to identify studies exploring the effects of kinase inhibition on: (1) neurotransmitter signaling pathways; (2) neurotrophic factors such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF); (3) neuroinflammation through glial cell modulation; and (4) neurogenic inflammation. Additionally, we assessed the impact of kinase inhibitors on tumor-induced axonogenesis and stress-related signaling. Clinical relevance was evaluated through analysis of preclinical models, human case studies, and outcomes from relevant clinical trials.

Kinase inhibitors were found to significantly modulate neural factors that facilitate tumor growth. Specifically, they can suppress neurotrophic signaling (e.g., NGF/TrkA, BDNF/TrkB), inhibit glial activation, reduce pro-inflammatory cytokine production, and block neurotransmitter-induced proliferation. Inhibition of stress-responsive kinases such as p38 MAPK and JNK also disrupted tumor-associated axonogenesis and inflammation. Clinical trials demonstrate improved outcomes in cancers such as glioblastoma, breast cancer, and pancreatic cancer when kinase inhibitors are employed with consideration of neural mechanisms.

These findings support the emerging concept of targeting the neural tumor microenvironment as a therapeutic strategy. Kinase inhibitors represent a dual-action approach, suppressing both cancer cell intrinsic growth pathways and the neural factors that sustain them. However, several challenges persist, including resistance mechanisms, variability in patient neural profiles, and off-target effects. Future research should focus on the development of neural-specific kinase inhibitors, the use of neural biomarkers for therapy selection, and the integration of neuro-oncology into personalized treatment plans.

Kinase inhibitors offer a promising frontier in cancer treatment by targeting neural mechanisms that contribute to tumor progression. While current evidence is encouraging, further investigation is required to optimize their use within neuro-oncology. Personalized approaches and novel targets within the neural-cancer axis will be essential for translating this strategy into clinical practice and improving long-term patient outcomes.

Polyamine metabolism is essential for cancer cell growth, with enzymes like ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC) playing key roles in polyamine (PA) biosynthesis. These polyamines (putrescine, spermidine, and spermine) regulate vital cellular processes, including DNA replication, protein synthesis, and cell cycle progression. Dysregulated polyamine metabolism is common in cancer, making ODC and AdoMetDC attractive therapeutic targets. This review highlights polyamines’ role in cancer and explores combination therapies targeting polyamine metabolism and critical signaling pathways for improved clinical outcomes.

A comprehensive analysis of both historical and recent literature on polyamine metabolism in cancer was performed using PubMed, which provides access to over 37 million citations from biomedical literature. Expression data for key polyamine biosynthetic enzymes, ODC and AdoMetDC, were obtained from the UALCAN portal - an interactive web resource for the analysis of cancer OMICS data. The IUPAC names of drugs and inhibitors targeting the polyamine pathway were retrieved from the PubChem database and used to generate molecular structures using the BIOVIA Draw 2025 program. Additionally, the ClinicalTrials.gov database was explored to identify ongoing and completed clinical research studies, as well as to gather detailed information on therapeutic agents targeting polyamine metabolism.

Aberrant polyamine metabolism in cancer is driven by oncogenic pathways like MYC, Akt, and mTOR. MYC upregulates ODC1, promoting polyamine dysregulation. Defects in enzymes such as MTA phosphorylase (MTAP) enhance cancer cell sensitivity to inhibitors of purine/pyrimidine synthesis and the ubiquitin-proteasome pathway, suggesting alternative therapeutic strategies.

Therapeutic strategies combining polyamine biosynthesis inhibition with targeting nucleotide synthesis or proteasome function have shown synergistic potential. However, the dual nature of polyamines - supporting both, tumor growth and ferroptotic cell death - poses a therapeutic challenge. Balancing these effects is key to designing effective interventions. Advancing this field requires not only selective inhibitors but also a deeper understanding of context-dependent polyamine functions in tumor biology.

Developing more potent inhibitors with improved drug-like properties is crucial for advancing polyamine-targeted therapies and positioning this field at the forefront of cancer research.

Colorectal cancer is an important cause of cancer-related mortality, necessitating innovative therapies to improve efficacy and reduce side effects. This study explores the potential of Cisplatin and Rutin-loaded nanoliposomes (Cis-NLs and Rut-NLs) for anti-colorectal cancer activity.

Cis-NLs and Rut-NLs were prepared using thin-film hydration, achieving encapsulation efficiencies of 95.5% and 62.5%, respectively. Drug release studies revealed controlled profiles, with Cis-NLs showing a complete release (100%) and Rut-NLs reaching 23.48% over 48 hours. Stability assessments demonstrated minimal changes in size, polydispersity index (PDI), and zeta potential over three months. Encapsulation efficiency decreased slightly for Cis-NLs (92.87%) and significantly for Rut-NLs (26.55%). Several tests were performed to evaluate the biological activity of this combination on colorectal cancer cells and HDF cells to check its selectivity.

In vitro cytotoxicity studies on HT29 colorectal cancer cells revealed IC50 values of 1.72 µg/mL for free Cisplatin, 2.35 µg/mL for Cis-NLs, >100 µg/mL for free Rutin, and 63.33 µg/mL for Rut-NLs. A combination of Cis-NLs and Rut-NLs reduced the IC50 to 2.2 µg/mL. Selective toxicity evaluation using human dermal fibroblasts showed an IC50 of 79.24 µM for cisplatin, reduced to 63.3 µM in Cis-NLs, with Rut-NLs demonstrating negligible toxicity.

Wound healing assays confirmed significant inhibition of cell migration, with wound closure reduced from 62.41% in controls to 34.35% in treated groups. Utilizing nanotechnology, liposomal formulations were synthesized to enhance drug delivery and therapeutic synergy.

These results highlight the potential of Cisplatin and Rutin-loaded nanoliposomes as a combination therapy for colorectal cancer.