Although cisplatin is a standard treatment for lung cancer, its effectiveness is often limited by tumor chemoresistance and severe side effects, driving the search for approaches that can restore drug sensitivity. Resveratrol (Res) exhibits anticancer properties, but its clinical application is hindered by poor stability and low bioavailability. This study investigated the chemosensitization effect of YI-7, a Res derivative with modified pharmacophore benzyloxy substitutions that sensitized to p53-dependent apoptosis triggered by cisplatin in human lung cancer cells.

Colorectal cancer remains a major cause of cancer mortality, driven by recurrence, metastasis, and resistance to therapy. Resveratrol (Res) has notable anticancer properties, yet its clinical utility is limited by poor stability and bioavailability. This study investigated the anticancer activity of SM-23, a Res derivative containing methoxy and ketone substitutions designed to enhance target binding and potency.

Cervical cancer remains a significant global challenge, necessitating novel therapeutic strategies beyond conventional radiotherapy and chemotherapy. The anticancer potential of natural compounds has recently garnered increased recognition. This study aimed to expand this knowledge by exploring the molecular mechanisms by which spinach extract (SE) influences the growth and survival of HeLa cervical cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to gemcitabine (GEM) resistance. This study aimed to establish a clinically relevant immunocompetent model to identify novel mediators of acquired GEM resistance.

Immune checkpoint inhibitors (ICIs) have been successful in treating advanced melanoma, yet, the 10-year melanoma-specific survival is only 52%. Our prior work using genetic linkage analysis revealed that the murine prolactin (PRL) locus associates with ICI response in C57BL/6 (B6)-syngeneic B16F0 melanoma. This was validated in F1 crosses of B6 with Collaborative Cross mice selected as potential non-responders or responders in the PRL locus and directly by coadministration of PRL with ICIs which slowed B16F0 growth compared with ICIs alone. This study uses Food and Drug Administration (FDA)-approved drugs that act on the dopamine D2 receptor (D2R), which inhibits PRL release from the pituitary, and suggests the potential of this receptor as a target to improve ICI outcomes.

Checkpoint inhibitor-induced liver injury (ChILI) is an immune-related adverse reaction, occurring in patients with cancer receiving immune checkpoint inhibitors (CPI). ChILI is currently managed with high doses of corticosteroids which carry their own risks and potential side effects, and the lack of available biomarkers makes monitoring patients at risk of developing ChILI a challenge. There is no specific test that distinguishes ChILI from other competing diagnoses such as acute autoimmune hepatitis (AIH) and idiosyncratic drug-induced liver injury (DILI) due to other medications.

We found epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) is up-regulated in liver cancer cells exposed to sorafenib for a long time using a bioinformatic tool. Here, the mechanism of EFEMP1 in sorafenib resistance of hepatocellular carcinoma (HCC) cells was explored.

Predicting severe adverse events (SAEs) in oncology is challenging because of complex therapies and patient heterogeneity. Traditional pharmacovigilance methods often fail to capture multifactorial risk patterns. Machine learning (ML) offers potential to identify subtle predictors of SAEs within large real-world data sets such as the US Food and Drug Administration Adverse Event Reporting System (FAERS). This study developed and validated an ML model to predict severe oncology-related adverse events and identify key risk factors using FAERS data.

Immune checkpoint inhibitor (ICI) cholangitis is an uncommon immune-related adverse event affecting the biliary ducts that is considered distinct from ICI hepatitis. This study examines whether the liver injury pattern or presence of histologic bile duct damage determines response to immunosuppression.

Patients with cancer have an elevated risk of chronic kidney disease (CKD); however, long-term alterations in kidney function among working-age individuals remain underexplored. This study aimed to evaluate differences in the rate of kidney function decline between working-age patients with cancer who received anticancer drug treatment and individuals without a history of cancer.

Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and debilitating adverse effect associated with the use of different anticancer drugs such as platinum compounds, taxanes, vinca alkaloids, and proteasome inhibitors. In the current experimental study, we investigate the neuroprotective effects of umbelliferone against oxaliplatin (OXA)-induced peripheral neuropathy in rats. Intraperitoneal administration of OXA (4 mg/kg) was used for induction of neurotoxicity in the rats. The rats subsequently received the oral administration of umbelliferone at a dose of 2.5, 5, and 10 mg/kg. The mechanical withdrawal threshold (MWT), cold allodynia testing, nerve conduction activity, body weight, cerebrum weight, cerebrum index, acetylcholinesterase (AchE), total protein, nitric oxide (NO), antioxidant, inflammatory cytokines, apoptosis, and inflammatory parameters were estimated. The different mRNA expressions were measured in the brain tissue. Umbelliferone treatment improved the MWT and reduced the cold allodynia. Umbelliferone significantly (P < 0.001) improved the nerve conduction velocity, along with the body weight, cerebrum weight, cerebrum index, and altered the levels of acetylcholinesterase (AchE), total protein, and nitric oxide (NO). Umbelliferone treatment altered the level of antioxidant parameters (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH), malonaldehyde (MDA)); inflammatory cytokines (interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), IL-10, IL-18); inflammatory parameters (cyclooxygenase-2 (COX-2), inducible nitric oxide synthetase (iNOS), prostaglandin E2 (PGE2), nuclear factor kappa B (NF-κB)); apoptosis parameters (caspase-3, caspase-9, Bcl-2 Associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), Bax/Bcl-2 ratio). Umbelliferone treatment altered the mRNA expression paraoxonase (PON)-1, PON-2, PON-3, and peroxisome proliferator-activated receptor δ (PPAR-δ). The findings clearly showed the neuroprotective effect of umbelliferone against OXA-induced neurotoxicity in rats via alteration of NF-κB, PPAR-δ, and mitochondrial apoptosis pathways.

Herein, isatin was derivatized into tetra-imine derivative (8d) using active reactants and their anticancer potential against human breast cancer cell (MCF-7), are reported. However, the analytical techniques named FT-IR, 1H and 13C NMR, were utilized to confirming of the synthesized compounds. In vitro investigation, MTT assay was demonstrated a dose-dependent decrease in MCF-7 cell viability, with an IC50 of 56 µM and 30% viability at 100 µM concentration as well. Morphological studies indicated apoptosis as the primary mechanism, evidenced by cell shrinkage, detachment, and reduced density. In silico analysis, the molecular docked complexes showed the strong binding affinity of 8d (-11.01 kcal/mol) to Human 3α-HSD3, with key interactions involving TYR24, ASN56, and TRP227. Molecular dynamics simulations (100 ns) confirmed complex stability, with minimal RMSD/RMSF variations and sustained hydrogen bonding. Radius of gyration and SASA analyses suggested increased protein compactness upon binding. MM-GBSA binding free energy was 11.29 ± 7.31 kcal/mol, dominated by van der Waals contributions. These results highlighted compound 8d as a promising scaffold for further development as a breast cancer therapeutic targeting Human 3α-HSD3.

Enzymatic hydrolysis is one of the effective methods used to obtain the bioactive peptides from marine resources. This study aimed to evaluate effect of the enzyme type (Food Pro PNL (FP), Corolase8000 (C8), and Corolase7089 (C7)) and biomass pretreatment level (whole starfish (SF), deproteinized (DPSF) as well as deproteinized and demineralized starfish (DPDMSF)) on the hydrolysate yield, degree of hydrolysis (DH), generated peptides' molecular weight (MW), and in vitro radical scavenging and antiproliferative effects. Regardless of the enzyme used, deproteinization reduced the hydrolysate yield (<8% dw/ww) and DH (<5%), but also adding demineralization, in combination with C8, resulted in an equal yield (15%) and DH (>40%) to SF. However, the protein content of hydrolysates from DPSF and DPDMSF was higher than that prepared from SF. C8 was not effective in hydrolyzing SF but was the only effective enzyme in hydrolyzing DPDMSF. The peptides' MW distribution strongly depended on the pretreatment and enzyme type, mostly ranging from 17 to 70 kDa. Glycine content was higher in hydrolysates from DPSF and DMDPSF, indicating their collagenous nature. Hydrolysates from DPSF, rich in collagenous peptides, showed medium MW but the highest radical scavenging activity. Only SF-FP hydrolysate, rich in non-collagenous peptides, showed antiproliferative activity against melanoma cancer cells. Overall, the findings demonstrate that upstream biomass pretreatment and enzyme selection directly govern the yield and bioactivity of starfish protein hydrolysates, providing a rational basis for designing starfish protein hydrolysates with targeted functional properties.

Chemical investigation of the marine sponge-derived Streptomyces xiamenensis 1310KO-148 afforded six polycyclic tetramate macrolactams (PTMs), including three known compounds (1-3) and three previously undescribed chlorohydrin-containing analogues, chlokamycins B-D (4-6). Their planar structures were elucidated by extensive analysis of 1D and 2D NMR spectra and HR-ESIMS data, while the relative configurations were assigned using NOESY correlations. The absolute configurations were further confirmed by electronic circular dichroism (ECD) calculations. Compounds 3-6 exhibited significant cytotoxic activity against 14 human cancer cell lines (GI50 = 2.68-24.92 μM) and antibacterial activity against Staphylococcus aureus (MIC = 16.00-32.00 μg/mL) and Micrococcus luteus (MIC = 4.00-32.00 μg/mL) among six tested bacterial strains.

Three new cyclic tetrapeptides (nectriatidels A-C, 1-3), two new curvularin analogs (6 and 7), and four known compounds (4 and 5, 8 and 9) were isolated from the marine-derived fungal-bacterial symbiont Aspergillus spelaeus GXIMD 04541/Sphingomonas echinoides GXIMD 04532, which was obtained from Mauritia arabica in shallow coastal waters. Their structures were elucidated through NMR spectroscopy and HRESIMS, and their absolute configurations were determined by Marfey's method and quantum chemical calculations. Compounds 1-5 showed moderate amphotericin B (AmB)-potentiating activity against Candida albicans. Compounds 7 and 8 exhibited significant activities against Mycobacterium tuberculosis, with MIC values of 32 and 16 μg/mL, respectively. Additionally, compounds 7 and 8 exhibited moderate cytotoxicity against human colorectal cancer cell lines DLD-1 and SW480, with IC50 values of 25~36 μM. Whole-genome sequencing of A. spelaeus revealed a 35.91 Mb assembly encoding 106 biosynthetic gene clusters (BGCs). antiSMASH analysis revealed that 79 of these BGCs (74.5%) displayed no significant similarity to known pathways in the MIBiG database, which is dominated by hybrid clusters, terpene, T1PKS, NRPS, and NRPS-like types. Genomic analysis identified the putative biosynthetic gene clusters for these metabolites and confirmed the fungal host as the predominant producer.

Nine new mycophenolic acid derivatives, penicacids O-W (1-9), two first-time reported natural products (10, 11), and five known compounds (12-16), were isolated from a marine-derived fungus Penicillium senticosum RCDB005 found in a South China Sea sediment sample. Their structures were determined using NMR, HRESIMS, and optical rotatory dispersion (ORD) spectra, electronic circular dichroism (ECD) calculations, X-ray crystallography, and modified Mosher's methods. Eight of these compounds were evaluated for anti-proliferative effects against nine human cancer cell lines and the IC50 values ranged from nM to μM levels. Compounds 5, 7-9 showed potent inhibition activity against MOLM-13 acute myeloid leukemia cells with IC50 values between 0.13 and 1.13 μM.

Marine-derived filamentous fungi are a rich source of structurally diverse and biologically active natural products. However, many biosynthetic gene clusters (BGCs) in fungi remain silent under standard conditions. In this study, we employed a metabolic shunting strategy to disrupt azaphilone biosynthesis in the marine-derived fungus Penicillium sclerotiorum E23Y-1A by deleting the pathway-specific regulator gene A00667. HPLC analysis revealed the emergence of new metabolite peaks in the mutant strain Δ667 compared to the wild type. Subsequent purification yielded seven compounds: the mutant produced two novel meroterpenoids sclerotilins A and B (1 and 2) along with the known steroids ergosta-5,7,22-trien-3β-ol (3) and cerevisterol (4), while the wild type yielded the known steroid (22E)-5α,8α-epidioxyergosta-6,22-dien-3β-ol (5) and two azaphilones geumsanol G (6) and 5-chloro-3-[(1E,3R,4R,5S)-3,4-dihydroxy-3,5-dimethyl-1-hepten-1-yl]-1,7,8,8a-tetrahydro-7,8-dihydroxy-7-methyl-(7R,8R,8aS)-6H-2-benzopyran-6-one (7). Bioactivity assays showed that compound 6 exhibited moderate antimicrobial activity against Staphylococcus aureus, and compound 3 displayed moderate cytotoxicity against five human cancer cell lines. These results demonstrate that A00667 is essential for azaphilone biosynthesis and that its disruption leads to the production of structurally distinct natural products, highlighting the potential of pathway engineering to redirect fungal metabolism to yield novel natural products.

Glioblastoma is a highly invasive primary brain tumor with a poor prognosis, highlighting the need for new therapeutic strategies. Toxins derived from Macrodactyla doreensis have attracted attention for their potential anticancer activity. This study evaluated the anticancer and cytotoxic effects of M. doreensis crude venom on two commonly used glioblastoma cell lines (U251 and LN229), which mirror the phenotype of primary tumors. Cell viability and proliferation were assessed using the CCK-8 assay and colony formation assay, while cell migration and invasion capabilities were detected via wound healing assay and Transwell assay. Annexin V/PI staining and PI-based cell cycle analysis indicated that the crude venom significantly induced cell apoptosis and caused S-phase arrest. Proteomic analysis combined with GO and KEGG enrichment analyses as well as bioinformatics approaches showed that M. doreensis crude venom inhibits glioblastoma cell proliferation by downregulating the expression of CDK2, RRM2, and CHEK1, thereby hindering cell cycle progression and regulating the p53 signaling pathway. Notably, the downregulation of these key glioblastoma-related target genes was validated by qPCR. In addition, network pharmacology analysis indicated that several peptide families present in the sea anemone crude venom, including ShK peptides, inhibitor cystine knot (ICK) peptides, and EGF-like peptides, exhibit notable antitumor potential. Combined with AlphaFold2-based structural modeling and molecular docking, these analyses further elucidated the potential molecular mechanisms underlying their interactions with key targets, such as MD-381 with RRM2, MD-322 with CDK2, and MD-429 with CHEK1. Collectively, these findings highlight the therapeutic potential of M. doreensis crude venom and lay a foundation for the subsequent isolation of novel peptides and their further development in glioblastoma treatment.

Background/Objectives: P-glycoprotein (P-gp, ABCB1/MDR1) is a key ATP-binding cassette transporter involved in multidrug resistance in cancer, limiting intracellular accumulation of various chemotherapeutic (CT) agents. Several antidepressants (ADs) have been shown to modulate P-gp function. This dual pharmacological profile raises the possibility of repurposing ADs as chemosensitizers to enhance anticancer drug efficacy. The objective of this review was to summarize the available evidence on the combined use of ADs and chemotherapeutics to overcome P-gp-mediated resistance. Methods: A systematic search was performed in PubMed, Scopus, and PsycInfo/PsycArticles databases using a comprehensive search string combining terms for P-gp, ADs, chemotherapy, and drug resistance. Inclusion criteria were preclinical or clinical studies investigating the effect of ADs in combination with chemotherapeutics on P-gp-mediated resistance in cancer models. Eleven relevant studies were identified and qualitatively analyzed. Results: Across diverse cancer models, including colon, breast, and multidrug-resistant cell lines, several ADs significantly enhanced the cytotoxicity of many chemotherapeutic agents. The proposed mechanisms involved downregulation of P-gp expression, inhibition of efflux activity, and increased intracellular drug accumulation. Conclusions: The combination of ADs with CT agents shows promising potential in overcoming P-gp-mediated multidrug resistance, enhancing antitumor efficacy in preclinical models. Further translational and clinical research is needed to validate these findings, optimize dosing strategies, and assess the risk-benefit profile in cancer patients, particularly those with comorbid depressive disorders.

ChemoNETosis represents a distinct form of therapy-induced innate immune activation, in which cytotoxic chemotherapy alters the tumor microenvironment (TME) in ways that attract and stimulate neutrophils, ultimately triggering the release of neutrophil extracellular traps (NETs). Unlike classical NETosis, which typically arises in response to infection or sterile inflammation, chemoNETosis is initiated by treatment-related danger signals and chemokine-cytokine loops that reshape the immune landscape and promote the formation of NET-rich metastatic niches. These NET structures serve not only as physical scaffolds but also as bioactive platforms enriched with proteases, reactive oxygen species, and enzymes capable of activating growth factors, collectively driving epithelial-mesenchymal transition, enhanced tumor cell plasticity, immune cell exclusion, changes in vascular permeability, and the development of chemotherapy resistance. While predominantly associated with tumor-promoting effects, chemoNETosis may, under specific genetic or metabolic conditions, contribute to antitumor responses, reflecting its context-dependent plasticity. In this review, we present what is, to our knowledge, the first in-depth synthesis of chemoNETosis across solid tumors, with a focus on key mechanistic nodes and translational perspectives.