Glioma remains difficult to treat because malignant cells show rapid proliferation, diffuse invasion, and frequent recurrence. This study investigated the direct antitumor effects of anlotinib in human glioma cells and examined whether these effects were associated with hepatocyte growth factor receptor/protein kinase B/mechanistic target of rapamycin (c-MET/AKT/mTOR) signaling, apoptosis-associated responses, mesenchymal-transition-related proteins, and autophagy-associated proteins. U87 and U251 cells were treated with anlotinib in vitro. Cell viability was assessed using Cell Counting Kit-8 assays, migration and invasion were evaluated using wound-healing and Transwell assays, Hoechst 33342 staining was used for qualitative assessment of apoptosis-associated nuclear morphology; and protein expression was analyzed by western blotting. Anlotinib reduced cell viability in a concentration-dependent manner, with estimated 24 h IC50 values of 68.00 μM for U87 cells and 45.53 μM for U251 cells. At lower concentrations, anlotinib reduced wound closure and Transwell invasion, decreased Vimentin, N-cadherin, and β-catenin expression, increased B-cell lymphoma 2 (BCL-2)-associated X protein, decreased BCL-2, altered poly(ADP-ribose) polymerase/caspase-9 expression, reduced total c-MET expression, and decreased AKT/mTOR phosphorylation. Analysis of autophagy-associated proteins showed an increased LC3-II/LC3-I and time-dependent p62 changes. Anlotinib may suppress malignant glioma-cell phenotypes in vitro. These phenotypic changes were associated with alterations in c-MET/AKT/mTOR pathway proteins, apoptosis-associated responses, mesenchymal-transition-related proteins, and autophagy-associated protein expression.
Oxaliplatin-induced peripheral vascular pain (OIVP) often requires central venous port placement. Conventional preventive strategies have limited efficacy, and the use of some effective analgesics is restricted. This single-center retrospective study evaluated the efficacy and safety of prophylactic tramadol. Electronic medical records of patients who received oxaliplatin-based chemotherapy via a peripheral intravenous line and experienced vascular pain [numerical rating scale (NRS) score ≥ 4] were reviewed. Patients who received prophylactic tramadol in a subsequent cycle were included (n = 23). The primary endpoint was the response rate (≥30% reduction in the NRS score from baseline). The secondary endpoint was the change in NRS score compared with the baseline score in the previous cycle. The response rate was 73.9% [95% confidence interval (CI): 51.6-89.8%]. The median NRS score for OIVP decreased significantly from 7.0 at baseline to 3.0 following tramadol administration (P < 0.0001). Administration greater than or equal to 60 min before infusion was associated with a higher response rate (88.9%; 95% CI: 51.8-99.7%) than administration at 30 min (64.3%; 95% CI: 35.1-87.2%), although this difference was not statistically significant (P = 0.208). Adverse events were mild, with grade 2 nausea reported in two (8.7%; 95% CI: 1.1-28.0%) patients. This exploratory study suggested that prophylactic tramadol was associated with a reduction in pain severity in OIVP, with a favorable safety profile. Thus, tramadol may be a promising and accessible prophylactic option, particularly when access to controlled analgesics is limited.
Breast cancer is a major cause of cancer-related mortality among women, and many patients eventually experience recurrence and progression to metastasis, despite advances in treatment. Estrogen-related receptor α (ERRα), an orphan nuclear receptor, is frequently overexpressed in aggressive breast cancer subtypes and is associated with poor prognosis and an increased risk of recurrence. This study aimed to investigate the role of transforming growth factor β (TGFβ) signaling in ERRα-mediated epithelial-mesenchymal transition (EMT), migration, and invasion in breast cancer cells. ERRα expression was modulated in breast cancer cells using XCT790-mediated inhibition, shRNA-mediated knockdown, and overexpression. Cell viability, clonogenicity, migration, invasion, EMT marker expression, and matrix metalloproteinase (MMP) activity were evaluated. TGFβ1 secretion and Smad signaling were also evaluated. XCT790-mediated inhibition or shRNA-mediated silencing of ERRα significantly reduced cell viability, migration, invasion, and MMP secretion in breast cancer cell lines, whereas ERRα overexpression upregulated migration, invasion, and MMP levels. ERRα suppression also upregulated the epithelial marker ZO-1 and downregulated mesenchymal markers, such as vimentin and β-catenin. This effect was associated with a significant decrease in TGFβ secretion, downregulation of TGFβ-mediated Smad signaling, and reduced expression of its downstream target ANGPTL4. These findings indicate that ERRα promotes EMT, migration, and invasion in breast cancer by upregulating TGFβ secretion and its signaling, underscoring its potential as a therapeutic target.
Capecitabine is an oral fluoropyrimidine prodrug widely used in the treatment of various malignancies, including colorectal cancer. While it is generally well-tolerated, rare and life-threatening toxicities can occur. Pneumonitis is an exceedingly rare complication associated with capecitabine monotherapy. A 36-year-old male with pT3N0 (stage IIA) colon adenocarcinoma underwent curative resection and was started on adjuvant capecitabine monotherapy. During the second cycle, the patient developed a cough and exertional dyspnea. Symptoms progressed during the third cycle, leading to hospitalization. Imaging revealed diffuse ground-glass opacities, and pulmonary function tests showed a severely reduced diffusion capacity of the lung for carbon monoxide (38% of predicted). Dihydropyrimidine dehydrogenase deficiency was ruled out. Based on clinical and radiological findings, a diagnosis of capecitabine-induced pneumonitis was made. Capecitabine was discontinued, and intravenous methylprednisolone (1 mg/kg) was initiated. The patient showed rapid symptomatic improvement and was discharged with a tapered steroid regimen. Follow-up imaging at 1 month showed complete resolution of pulmonary opacities. The patient remains in remission at a 3-year follow-up. Although capecitabine-induced pneumonitis is remarkably rare, it carries a risk of significant morbidity. Clinicians should maintain a high index of suspicion for drug-induced pulmonary toxicity in patients presenting with new respiratory symptoms during capecitabine therapy, as early recognition and treatment are crucial for recovery.
Pancreatic cancer is a highly lethal digestive malignancy characterized by insidious onset and rapid progression. Approximately 80% of patients are diagnosed at an advanced stage with metastasis, missing the opportunity for radical surgery, and chemotherapy remains the main palliative treatment. Its incidence is rising annually, highlighting the urgent need for novel therapeutic strategies. MLN4924 (Pevonedistat), a first-in-class NEDD8-activating enzyme inhibitor, exhibits promising antitumor activity in various cancers, yet its role and mechanism in pancreatic cancer remain largely undefined. Potential hub targets of MLN4924 in pancreatic cancer were screened using Swiss Target-Prediction and Gene-Cards databases. Western blot was used to detect the expression of hub genes and the activity of the prostaglandin G/H synthase 2 (PTGS2)-epidermal growth factor receptor (EGFR)-phosphatidylinositol 3-kinase (PI3K)/RAC-gamma serine/threonine-protein kinase (Akt)/serine/threonine-protein kinase (mTOR) axis following MLN4924 intervention. CCK-8, EdU, and wound-healing assays were performed to evaluate cell proliferation and migration after MLN4924 treatment. Furthermore, PTGS2 knockdown via siRNA transfection was applied to verify its effects on EGFR-PI3K/Akt/mTOR pathway activity, malignant phenotypes, and gemcitabine sensitivity in pancreatic cancer cells. We identified four hub genes (CASP3, PTGS2, MMP9, and MAPK8) of MLN4924 in pancreatic cancer. We validated that MLN4924 suppressed proliferation and migration of pancreatic cancer cells, downregulated hub gene expression, and inhibited the PTGS2-mediated PI3K/AKT/mTOR signaling pathway. Furthermore, siRNA-mediated silencing of PTGS2 phenocopied the inhibitory effects of MLN4924 on cell proliferation. Notably, both MLN4924 and PTGS2 knockdown significantly enhanced the chemosensitivity of pancreatic cancer cells to gemcitabine. Collectively, our results demonstrate that MLN4924 exerts antitumor effects in pancreatic cancer by targeting the PTGS2-EGFR-PI3K/AKT/mTOR axis, providing a mechanistic rationale for its clinical application in pancreatic cancer therapy.
Tertiary lymphoid structures (TLS) are associated with prognosis in solid tumours. Their value for predicting axillary nodal involvement in oestrogen receptor-positive luminal breast cancer remains uncertain. Three published TLS signatures were scored by single-sample gene set enrichment analysis in oestrogen receptor-positive luminal tumours. The Cancer Genome Atlas Breast Invasive Carcinoma cohort (TCGA-BRCA) included 632 cases, of which 379 met strict consensus. METABRIC included 1086 cases, of which 663 met strict consensus. Logistic models adjusted for age and pathological tumour stage. Strict consensus, majority vote, and continuous scores were compared. Performance assessment included bootstrapped changes in area under the receiver-operating-characteristic curve, Brier scores, calibration, and decision-curve analysis. Survival was evaluated in METABRIC and explored in TCGA-BRCA. Strict-consensus TLS status was not associated with nodal positivity in TCGA-BRCA (adjusted odds ratio: 0.95, 95% confidence interval: 0.62-1.45, P = 0.822). METABRIC was similar (odds ratio: 0.76, 95% confidence interval: 0.55-1.06, P = 0.105). Full-cohort METABRIC analyses detected small majority-vote and continuous-score associations, absent in TCGA-BRCA. Across specifications, bootstrapped changes in area under the receiver-operating-characteristic curve ranged from 0.0002 to 0.0089, with minimal Brier-score improvement and no stable decision-curve benefit. In METABRIC, the univariable overall survival association attenuated after age adjustment (hazard ratio: 1.33-1.10). TCGA-BRCA survival analyses were nonsignificant. TLS transcriptomic signals showed small, cohort-dependent associations with nodal status but no reproducible or clinically meaningful incremental predictive value. These data do not support replacing sentinel lymph node biopsy with a TLS signature in oestrogen receptor-positive luminal breast cancer.
Dysregulation of the phosphoinositide 3-kinase/protein kinase B (AKT)/mechanistic target of rapamycin pathway is a hallmark of breast cancer, making AKT a focus of therapeutic interest. AKT inhibitor-IV is a benzimidazolium compound that inhibits AKT phosphorylation, but its activity and binding mechanism in breast cancer cells have not been characterized in detail. We compared AKT inhibitor-IV with tamoxifen in MCF-7 cells. Cell viability after 24-h treatment was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay (AKT inhibitor-IV: 0.1-5 μM; tamoxifen: 5-50 μM); apoptotic death was quantified by nucleosome ELISA; and AKT1, BCL-2, BAX, and CASP3 mRNA levels were measured by quantitative real-time PCR. Both compounds were docked into the ATP-binding pockets of 3-phosphoinositide-dependent protein kinase-1 (PDK1) (PDB 1H1W) and AKT1 (PDB 3MVH) using AutoDock Vina v1.2.6. AKT inhibitor-IV reduced viability with an IC50 of 1.1 μM, compared with 5.2 μM for tamoxifen, and induced 5.9-fold apoptosis enrichment versus 3.65-fold for tamoxifen. AKT inhibitor-IV downregulated AKT1 (0.32-fold) and BCL-2 (0.55-fold) and upregulated BAX (5.97-fold) and CASP3 (6.43-fold) mRNA; tamoxifen showed qualitatively similar but quantitatively weaker transcriptional changes. Docking returned affinities of -9.91 kcal/mol for PDK1 and -9.66 kcal/mol for AKT1, with AKT inhibitor-IV contacting catalytic-core residues of both kinases. AKT inhibitor-IV was more potent than tamoxifen in this in-vitro setting and warrants further preclinical evaluation. Because MCF-7 cells carry the CASP3 exon 3 deletion and lack functional caspase-3 protein, the observed CASP3 mRNA upregulation reflects transcriptional reprogramming rather than restored executioner activity. The modest docking difference requires biochemical confirmation before any PDK1-versus-AKT1 selectivity claim can be established.
Growth differentiation factor-11 (GDF11) is an important member of the transforming growth factor-β superfamily and plays an important role in tumor progression. However, its role and prognostic value in acute myeloid leukemia (AML) have not been reported. We overexpressed GDF11 to investigate the effect of GDF11 on the behavior of AML cells. The effect of GDF11 on chemotherapy sensitivity was investigated in HL60 cells treated with 10 μM daunorubicin (DNR). Cell viability was detected using the cell counting kit-8 assay. Western blot was performed to analyze the expression levels of target proteins. GDF11 was associated with poor overall survival of AML patients. The proliferation of HL60 cells was inhibited by the transfection of pcDNA3.1-GDF11. GDF11 overexpression upregulated the expression of caspase3-p17 and Bax, while downregulating the Bcl-2 level. Importantly, the decreased cell proliferation and induced apoptosis by DNR were enhanced by GDF11 overexpression. Cathepsin S (CTSS) expression was inhibited by GDF11 in HL60 cells. The overexpression of CTSS attenuated the enhancement of GDF11 on chemotherapy sensitivity. In addition, CTSS activated the extracellular signal-regulated kinase 1 and 2 signaling pathway and inhibited endoplasmic reticulum stress in AML cells. In conclusion, GDF11 inhibited the growth and increased chemosensitivity through inhibiting CTSS expression in AML cells, providing potential therapeutic targets for AML treatment.
Refractory metastatic colorectal cancer (mCRC) management is further complicated when fluoropyrimidine-based therapy is contraindicated, leaving few systemic options. We present a 57-year-old man with KRAS G13D-mutant, liver-dominant metastatic rectal adenocarcinoma and recurrent fluoropyrimidine-associated coronary vasospasm precluding 5-fluorouracil and capecitabine. After multimodal first-line therapy and regorafenib, trifluridine/tipiracil (TAS-102) plus bevacizumab was initiated and integrated with liver-directed treatments for oligoprogressive disease. This combined strategy achieved approximately 16.6 months of disease control, substantially exceeding the median progression-free survival reported in the SUNLIGHT trial, with manageable hematological toxicity and preserved performance status. This case highlights the value of TAS-102 plus bevacizumab combined with focal liver-directed therapy as a feasible long-term strategy for selected patients with oligoprogressive mCRC when fluoropyrimidines cannot be used.
Primary splenic angiosarcoma (PSA) is a rare vascular malignancy with a poor prognosis and limited therapeutic options. A 62-year-old man with metastatic PSA underwent splenectomy followed by first-line paclitaxel, achieving stable disease for 7 months. Disease progression manifested as hepatic and bone marrow metastases with tumor-induced hepatic failure and refractory thrombocytopenia. Sequential treatment with liposomal doxorubicin, eribulin, toripalimab, and lenvatinib failed to control the disease failed to control the disease. Genomic profiling identified a PIK3CA p.P471L missense mutation. A combination regimen of inavolisib (a selective PI3Kα inhibitor) and lenvatinib was initiated. Bilirubin levels normalized, and platelet counts recovered within 2 weeks; follow-up MRI confirmed radiological stabilization. At 16 months postdiagnosis, the patient remains alive on this regimen, though long-term durability of response has yet to be determined. To our knowledge, this is the first reported use of inavolisib in angiosarcoma. The rapid biochemical and radiological response observed in this PIK3CA-mutated PSA supports early genomic profiling to identify actionable alterations and warrants prospective evaluation of combined phosphoinositide 3-kinase and vascular endothelial growth factor pathway inhibition in refractory angiosarcoma.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally. Hepatic arterial infusion chemotherapy with 5-fluorouracil (5-FU) have been considered; however, it has limited survival benefits because of unbearable toxicity. Hence, a series of 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) prodrugs was designed and synthesized using ProTide technology. By favorable membrane permeability and bypassing enzymatic activation pathway of 5-FU to FdUMP, DL series of ProTide prodrugs circumvented mechanisms of 5-FU resistance and avoided the generation of associated toxic catabolites, resulting in enhanced anti-HCC efficacy and weak toxicity. Antiproliferative activity of compounds was evaluated in both human HCC cell lines and normal hepatocytes. Further anti-HCC activity was assessed in nude mice xenografted human HepG2, HUH7, or histidine triad nucleotide-binding protein 1 (HINT1) knockdown HUH7 cells orthotopically or subcutaneously. Mechanistic studies involving HINT1-silenced cells and co-administration with HINT1 upregulation by taraxasterol were conducted to validate the mode of action. Compound DL-2 effectively inhibited HCC cell growth but exhibited minimal cytotoxicity toward normal hepatocyte cell lines. DL-2 exhibited anticancer activity through bioactivation into FdUMP by hepatic HINT1. Comparatively, DL-2 weakly inhibited the orthotopic xenograft derived from HINT1-silenced human HUH7 cells. Systemic use of DL-2 did not produce significant toxicity in mice. In conclusion, we discovered an orally active and liver-targeted dual prodrug of FdUMP for the treatment of HCC. DL-2 is a promising drug used as a substitute for hepatic arterial infusion chemotherapy regimen.
Liver cancer is a malignant tumor with high incidence and mortality rates globally. Existing therapeutic methods have certain limitations in terms of efficacy, safety, and applicability, creating an urgent need for the development of new treatment strategies. Drug repurposing, which explores new indications for already approved drugs, offers significant advantages in reducing research and development costs and shortening development timelines. This study utilized a multimodal neural network model to integrate molecular fingerprints and molecular graphs to construct a drug-target interaction prediction system for liver cancer targets. A large-scale virtual screening of The US Food and Drug Administration-approved drugs was conducted, followed by molecular docking and molecular dynamics simulations to analyze binding stability. The screening identified 17 potential antiliver cancer drugs. Further verification of their in-vitro activity was performed through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and wound healing assays in MHCC97-H, HepG2, and Huh7 cell lines, revealing that Manidipine and Vildagliptin exhibited significant cytotoxicity and migration inhibition. These results demonstrate the feasibility of the proposed screening workflow and provide a set of candidate molecules for further mechanistic investigation in liver cancer drug repurposing.
Hairy cell leukemia (HCL) is a rare mature B-cell malignancy characterized by the BRAF V600E mutation. TP53 abnormalities in HCL are associated with poor response to standard therapies and a higher risk of relapse. We report an elderly male patient diagnosed with classical HCL (BRAF V600E-positive) who also presented with a TP53 deletion detected by fluorescence in situ hybridization (FISH) and bone marrow fibrosis. The patient was treated with one cycle of cladribine combined with low-dose rituximab (100 mg). The treatment was well tolerated. At the 7-month follow up, the patient achieved complete molecular remission, characterized by normalized blood counts, recovery of bone marrow morphology, disappearance of the TP53 deletion by FISH, negative minimal residual disease by flow cytometry, and reversal of bone marrow fibrosis from MF-2 to MF-0. This case suggests that the combination of cladribine and low-dose rituximab may be an effective therapeutic strategy for classical HCL with TP53 abnormality, enabling deep molecular response and reversal of associated bone marrow fibrosis. Further prospective studies are warranted to validate these findings.
Despite the clinical benefits of immune checkpoint blockade in hepatocellular carcinoma (HCC), therapeutic efficacy remains limited due to persistent immune evasion. SENP3, a SUMO2/3-specific protease sensitive to redox regulation, has emerged as a critical regulator of protein homeostasis and immune modulation. This study investigates how SENP3 regulates programmed death-ligand 1 (PD-L1) stability through SUMOylation to facilitate immune escape in HCC. We performed comprehensive molecular and functional analyses in HCC cell lines using SENP3 manipulation strategies. PD-L1 expression and SUMOylation status were evaluated by Western blotting and Ni-NTA pulldown assays. Protein interactions were examined through coimmunoprecipitation. Functional immune assays included T cell cytotoxicity measurements using coculture systems, colony formation assays to quantify tumor cell survival, cytokine profiling by ELISA, and granzyme B (GzmB) expression analysis in CD8⁺ T cells via flow cytometry. Clinical samples and experimental models demonstrated significant SENP3 overexpression in HCC. SENP3 knockdown reduced PD-L1 abundance while enhancing T cell-mediated tumor killing, pro-inflammatory cytokine secretion, and cytotoxic GzmB expression in CD8⁺ T cells. Mechanistic studies revealed that SENP3 directly interacts with PD-L1 and catalyzes its deSUMOylation, thereby extending PD-L1 protein half-life. Importantly, SENP3 overexpression rescued the immunostimulatory effects of PD-L1 knockdown, confirming the specificity of this regulatory pathway. Our findings establish SENP3 as a novel posttranslational regulator of PD-L1 that promotes immune evasion in HCC through direct deSUMOylation and stabilization of PD-L1 protein. Therapeutic targeting of SENP3 may overcome resistance to immune checkpoint inhibitors in HCC by restoring antitumor immunity.
Bladder cancer (BCa) patients frequently develop resistance to platinum-based therapies, particularly cisplatin. The link between chemoresistance and glycolysis has been well documented. Emerging evidence suggests that Rac family small GTPase 3 ( RAC3 ) may play significant roles in cisplatin resistance. This study investigated the underlying molecular mechanisms. Clinical specimens (cisplatin-sensitive/resistant BCa tissues and matched adjacent normal tissues) were collected from hospital. Cisplatin-resistant cell lines [T24-derived cisplatin-resistant cells (T24-DDP) and 5637-derived cisplatin-resistant cells (5637-DDP)] were generated through stepwise dose escalation. RAC3 , Myc-binding protein 2 (MYCBP2 ), P21-activated kinase 1 ( PAK1 ), Ki-67, and glycolysis markers were analyzed by quantitative PCR, immunohistochemistry, and Western blot. RAC3 ubiquitination was assessed via co-immunoprecipitation. Cell viability, apoptosis, and glycolytic metabolism were evaluated using the cell counting kit-8 assay, terminal deoxynucleotidyl transferase deoxyuridine triphosphate/flow cytometry, and ATP/lactate assays, respectively. Glycolytic flux was measured by extracellular acidification rate. Additionally, BCa xenograft models were established for in-vivo detection. Elevated RAC3 expression and glycolytic activity were observed in BCa tissues, with further augmentation in cisplatin-resistant tumors. RAC3 overexpression promoted cell viability, glycolysis, invasion, and migration in cisplatin-treated T24 and 5637 cells. Conversely, RAC3 knockdown exerted the opposite effects and restored cisplatin sensitivity in resistant T24-DDP and 5637-DDP cells. Notably, the sensitizing effect of RAC3 knockdown was reversed by PAK1 overexpression. Furthermore, MYCBP2 regulated RAC3 stability, as MYCBP2 overexpression enhanced RAC3 ubiquitination, suppressed glycolysis, and sensitized resistant cells to cisplatin. These effects were abrogated by the proteasome inhibitor MG132, confirming proteasome-dependent degradation of RAC3 . MYCBP2 -mediated ubiquitination of RAC3 modulates the PAK1 /pyruvate dehydrogenase E1 subunit alpha axis to regulate glycolytic activity, ultimately determining cisplatin sensitivity in BCa.
Phosphodiesterase 4B (PDE4B), an isoform of cyclic nucleotide phosphodiesterases, is integrated into cell membranes and hydrolyzes cyclic AMP in specific cellular compartments. Overexpression of PDE4B has been observed in hematological and gastrointestinal tumors harboring KRAS mutations, leading to the disruption of cell cycle regulation. Utilizing molecular docking, we identified 3-aminoisoquinolines as potential selective PDE4B inhibitors. Phenotypic screening on HKe3-KRAS cell lines confirmed that PDE4B is a selective target for these novel 3-aminoisoquinolines. We employed molecular docking and calculated ligand efficiency as predictive tools for methylthiazoltetrazolium assay activity to reduce the combinatorial library size. Six active compounds (047, 048, 086, 089, 091, and 099) were screened. Active compounds 047, 048, 086, 089, and 091 demonstrated selectivity toward HKe3-mtKRAS over wild-type cells. This 'synthetic lethality-like' approach was effective in predicting the anticancer properties of these compounds in KRAS-mutated cell lines. NCI-DTP 60 cell lines assays confirmed the activities of 047, 048, and 089. Compound 089 showed strong cytotoxicity against HCT-116 cells inhibitory concentration (IC50) = 1.6 μM, growth inhibition (GI50) = 0.53 μM, and an inhibitory concentration (IC50) against PDE4B = 2.5 μM. In addition, 089 exhibited good tolerability in a nude mouse HCT-116 xenograft model, but it was less effective at a dose of 40 mg/kg compared with Apremilast at a dose of 30 mg/kg in 8-s day's assay. While 089 had lower in-vivo efficacy than apremilast, its novel 3-aminoisoquinoline scaffold and high tolerability make it a superior candidate for further optimization.
D430-2307 is a novel small-molecule compound identified through virtual screening of the Chemdiv database that markedly inhibited the proliferation of both MCF-7 and MDA-MB-231 breast cancer cells. In the present study, the anticancer activity and underlying molecular mechanisms of D430-2307 were investigated. Thiazolyl blue, colony formation, wound healing, and transwell assays were performed to assess the effects of D430-2307 on breast cancer cell proliferation, migration, and invasion. To elucidate the underlying mechanisms, flow cytometry, Western blotting, and fluorescence staining were performed to analyze cell-cycle distribution, apoptosis, and intracellular reactive oxygen species (ROS) levels. In addition, network pharmacology, transcriptomics, and bioinformatics analyses were integrated to identify core targets and associated pathways, while molecular docking was performed to verify target-ligand interactions. The results demonstrated that D430-2307 significantly inhibited breast cancer cell proliferation, migration and invasion, induced G 0 /G 1 cell cycle arrest, downregulated CDK4/6 expression, and promoted apoptosis through modulation of the Bax/Bcl-2 ratio and activation of caspase-3/7 signaling. Furthermore, D430-2307 suppressed the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway via elevation of intracellular ROS levels. These findings suggest that D430-2307 exerts antitumor effects through ROS-mediated suppression of PI3K/AKT signaling, G 0 /G 1 cell cycle arrest, and apoptosis induction, providing a foundation for the development of novel anti-breast cancer therapeutics.
The efficacy of paclitaxel (PTX), an important chemotherapy drug in non-small-cell lung cancer (NSCLC) cells, is limited by its resistance. APG-1252 has an inhibitory role in cancer and can inhibit myeloid cell leukemia 1 (MCL-1) to enhance chemotherapy drugs' antitumor effect. Therefore, this research further investigated whether APG-1252 could enhance the anticancer role of PTX by regulating MCL-1. NSCLC cells were treated with drugs. Cell viability was determined using the cell counting kit-8 assay. The cell apoptosis was examined using flow cytometry and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling staining. The abilities of cells to migrate, invade, and proliferate were examined using transwell and colony formation assays, as needed. The expression levels of extracellular regulated protein kinases (ERK), phosphorylated ERK (p-ERK), and MCL-1 were quantified by Western blot. APG-1252 and PTX decreased the NSCLC cells' viability. APG-1252 and PTX induced cell apoptosis and inhibited the cells from migrating, proliferating, and invading. APG-1252 and PTX suppressed the expression of p-ERK and MCL-1. Besides, APG-1252 enhanced the anticancer role of PTX in NSCLC cells. Ro 67-7476, a p-ERK agonist, had an opposite role to the combination of APG-1252 with PTX in NSCLC cells. Additionally, Ro 67-7476 abolished the anticancer role of the combination of APG-1252 with PTX in the biological functions of NSCLC cells. APG-1252 enhanced the anticancer role of PTX in NSCLC cells by suppressing the ERK/MCL-1 pathway. This work provided the theoretical basis for the APG-1252 application.
Advanced hepatocellular carcinoma (HCC) with extensive metastases is associated with a poor prognosis, highlighting the need for individualized, multimodal treatment strategies. We present the case of a 54-year-old male with advanced HCC (cT3NxM1, Child-Pugh B) and spinal as well as bilateral pulmonary metastases who experienced disease progression after multiple lines of therapy. A dynamically adjusted, multidisciplinary regimen was implemented, incorporating transarterial chemoembolization (TACE), surgery, immunotherapy, and targeted therapy. The final regimen - combining nivolumab plus ipilimumab (O+Y) with TACE and lenvatinib - achieved a partial response in lung metastases, with a progression-free survival exceeding one year and overall survival of over 24 months. This case underscores the therapeutic potential of O+Y in later-line settings and demonstrates the clinical value of an integrated, personalized treatment paradigm for advanced HCC.
