Anti-Cancer Drugs最新文献

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) effectively treat EGFR-mutant lung adenocarcinoma, demonstrating initial efficacy but eventually leading to acquired resistance. Small cell transformation is a rare resistance mechanism to EGFR-TKIs in lung adenocarcinoma, which can complicate clinical diagnosis and treatment. We present a patient with lung adenocarcinoma who underwent a prior pneumonectomy and adjuvant chemotherapy and was treated with osimertinib after the recurrence of lung cancer. Small cell transformation occurred approximately 20 months after starting osimertinib treatment. After this transformation, the patient underwent lung radiotherapy and cisplatin-etoposide chemotherapy, which stabilized the disease. Following the confirmation of small cell lung cancer (SCLC) via thyroid puncture, treatments with irinotecan, irinotecan plus atezolizumab, thyroid radiotherapy, adrenal radiotherapy, and head radiotherapy were sequentially administered, yet the disease continued to progress. The patient succumbed to the disease in May 2023 because of progression and organ failure, with an overall survival of 52.7 months, including 16 months post small cell transformation. This case highlights the possibility of osimertinib causing lung adenocarcinoma to transform into SCLC and underscores rebiopsies' importance in identifying resistance mechanisms to EGFR-TKIs. Increased levels of neuron-specific enolase and pro-gastrin releasing peptide can signal early transformation into SCLC.

Wnt1-inducible signaling pathway protein 1 (WISP1) promotes breast cancer. The Hippo signaling pathway demonstrates a potential connection with WISP1, necessitating an exploration of their interaction. This study hypothesized that WISP1 boosts breast cancer by modulating the Hippo signaling pathway. The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were used to analyze WISP1 expression and Hippo signaling in breast cancer patients. WISP1, yes-associated protein (YAP), and domain family member 4 (TEAD4) were overexpressed or silenced in breast cancer cells. Epithelial-mesenchymal transition (EMT), and chemoresistance of breast cancer cells were evaluated. Immunofluorescence, PCR, immunoprecipitation, and western blot were used to detect the expression of WISP1 and key Hippo signaling factors and their interactions. Enrichment analysis indicated activation of WISP1 and Hippo signaling pathway and correlated with a worse prognosis in breast cancer. WISP1 overexpression facilitated EMT and chemotherapy resistance in breast cancer. Importantly, overexpression of WISP1 promoted YAP's nuclear translocation. TEAD4 expression in YAP precipitates from nuclear of WISP1-overexpressing MCF-7 cells increased. The promoting effect of WISP1 on breast cancer was counteracted by silencing YAP or TEAD4. Moreover, in WISP1 small interfering RNA-transfected MCF-7 cells, p-YAP expression increased, while interaction between YAP and TEAD4 decreased. WISP1 silencing led to ubiquitin increase and TEAD reduction in the p-YAP precipitates. In conclusion, WISP1 promotes YAP nuclear translocation and binding with TEAD4 by inhibiting YAP phosphorylation, reducing ubiquitin recruitment, and participating in transcriptional regulation in breast cancer.

Triple-negative breast cancer (TNBC) is highly prone to early relapse and metastasis following standard treatment. CXCL8 is a key factor in tumor invasion and metastasis, but its role in TNBC prognosis and clinicopathological correlations remains poorly understood. This study investigated CXCL8 expression and its clinical significance in TNBC to develop a prognostic nomogram for guiding intensive treatment and follow-up strategies. Public datasets from the gene expression omnibus public datasets platform were analyzed to assess CXCL8 expression. Additionally, paraffin-embedded TNBC specimens collected from our hospital were examined using immunohistochemistry to explore the relationship between CXCL8 expression and clinicopathological features. Survival analysis was performed to evaluate whether CXCL8 serves as an unfavorable prognostic biomarker for TNBC patients. Univariate Cox regression analysis was conducted to identify prognostic factors. Based on these findings, a nomogram was developed to predict TNBC progression risk. CXCL8 expression was significantly higher in TNBC tissues than in adjacent normal tissues ( P  < 0.05). Among 122 TNBC patients, 46 were CXCL8-positive and 76 were CXCL8-negative. CXCL8 expression was significantly associated with N stage ( P  < 0.05). Progression-free survival (PFS) was markedly shorter in the CXCL8-positive group compared with the CXCL8-negative group ( P  < 0.001). Univariate Cox regression identified N1-3, M1, and CXCL8 positivity as significant risk factors for disease progression. A nomogram incorporating these variables (N, M, and CXCL8) was constructed to predict PFS. Time-dependent receiver operating characteristic curve analysis at 12-, 36-, and 48-month demonstrated strong predictive performance, with area under the curve values of 0.857, 0.839, and 0.795, respectively. CXCL8 is highly expressed in TNBC and promotes lymphatic metastasis, serving as an unfavorable prognostic factor. The developed nomogram offers a valuable tool for guiding personalized treatment and follow-up strategies in TNBC patients.

Eugenol, a phenolic natural product with diverse pharmacological activities, remains unexplored in liver cancer. Using network pharmacology, we investigated eugenol's therapeutic mechanisms in liver cancer. We obtained eugenol's molecular structure from PubChem and screened its targets using similarity ensemble approach in Swiss Target Predictiondatabases. Overlapping genes with liver cancer-related genes from GeneCards were identified. Protein-protein interaction networks, Gene Ontology annotations, and Kyoto Encyclopedia of Genes and Genomes pathway analyses were conducted. A target-pathway network revealed eugenol's interaction with 122 liver cancer-related genes. Molecular docking confirmed eugenol's high affinity for mitochondrial nicotinamide adenine dinucleotide, reduced form (NADH) dehydrogenase 1 (MT-ND1), AKT1, NDUFB7, and NADH dehydrogenase (complex I) subunit S3 (NDUFS3). Expression levels of these targets in normal liver and liver cancer tissues were examined using GEPIA2 and HPA databases. The CCK-8 assay and colony formation assay demonstrated that eugenol significantly inhibited the proliferation of hepatocellular carcinoma cells. Western blot analysis confirmed that eugenol upregulated MT-ND1 while downregulating the expression of targets such as AKT1, NDUFB7, and NDUFS3. Furthermore, it was found that eugenol could influence the expression of the AKT1 target through the AKT/p70 S6K pathway. This study provides new insights into the potential mechanisms of eugenol in liver cancer and offers novel perspectives for network-based liver cancer research.

Imatinib mesylate (IM) is a first-line therapy for chronic myeloid leukemia (CML) and exhibits good therapeutic effects, but not in all patients with CML owing to drug resistance. Our previous study showed that Cyr61 plays a key role in IM resistance in CML cells. Paeoniflorin (PF) is a bioactive compound isolated from the traditional Chinese medicine Paeonia lactiflora Pall that displays anticancer activity. Little is, however, known regarding the role of PF in IM-resistant CML cells. This study aimed to evaluate whether PF could decrease Cyr61 production and improve IM-resistant CML cell sensitivity to IM and to investigate the underlying mechanisms. CML cell lines (K562 and KCL22) and IM-resistant cell lines (K562G and KCL22R) were used as CML study models. Cyr61 expression was assessed in both parental and IM-resistant CML cells by western blotting, real-time quantitative PCR , and ELISA. Lentiviral vectors were used to induce the knockdown of Cyr61 expression, followed by a comprehensive evaluation of cell proliferation and apoptosis. The results showed that PF decreased the production of Cyr61 in the presence of IM by inhibiting extracellular regulated protein kinases 1/2 activation. PF significantly decreased the IC50 value of IM and increased IM-induced apoptosis of IM-resistant CML cells. Importantly, PF also improved the sensitivity of CML cells to bosutinib and dasatinib via inhibition of Cyr61 production. In conclusion, we report for the first time that PF may effectively improve the sensitivity of IM-resistant CML cells to IM, bosutinib, and dasatinib, at least in part, by subsequently downregulating Cyr61.

Herein, we report a case of occult epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma complicated by prostatic metastasis. A 75-year-old male with >30 years of smoking history presented with lower back pain as the initial symptom. Respiratory symptoms, including cough and sputum production, were absent. PET-computed tomography revealed the presence of bone and prostatic metastases, without any lung abnormalities. Biopsies of the space-occupying bone and metastatic lesions suggested that the metastases originated from primary lung adenocarcinoma. Genetic testing indicated EGFR 21L858R(+). The patient had an abnormal serum carcinoembryonic antigen level but a normal prostate-specific antigen level. Following a multidisciplinary discussion, a diagnosis of occult primary lung adenocarcinoma complicated by bone and prostatic metastases (TxN0M1b, Stage IVB) was considered. Following targeted therapy with oral osimertinib, the patient achieved a partial response, with alleviation of pain symptoms alleviated and normalization of carcinoembryonic antigen levels. In the absence of tissue biopsy, such cases can often be misdiagnosed as prostate cancer complicated by multiple bone metastases. Hence, the present case highlights the importance of comprehensive diagnostic testing, including tissue biopsy, to accurately identify the underlying cause of metastatic disease.

The combination of anlotinib with immune checkpoint inhibitors (ICIs) has become a common treatment modality in clinical practice. However, the optimal dose of anlotinib to use remains unclear. We collected patients with advanced non-small cell lung cancer (NSCLC) who received programmed cell death-1 blockade combined with different dose of anlotinib as second-line or later line therapy. Subsequently, the efficacy and safety of the combination therapy as well as subgroup analyses of different doses of anlotinib were analyzed. Cox regression was performed to analyze significant factors correlated with progression-free survival (PFS) and overall survival (OS). A total of 50 eligible patients with NSCLC who received anlotinib combined with ICIs therapy were included, of which 27 received low-dose anlotinib (8 mg), and 23 were administered high-dose anlotinib (12 mg). The median PFS (mPFS) and the median OS (mOS) for all patients were 8.3 months [95% confidence interval (CI): 6.3-10.3] and 17.6 months (95% CI: 16.5-18.7), respectively. Subgroup analyses showed that patients treated with 8 mg of anlotinib plus ICIs had significantly longer mPFS than those treated with 12 mg of anlotinib plus ICIs (8.7 vs 6.7 months, P  = 0.016). The overall incidence of adverse events was 68.0%, and the most common adverse events of all grades were hypertension. Meanwhile, the incidence of adverse events was higher for 12 mg of anlotinib plus ICIs than that of 8 mg of anlotinib plus ICIs (82.6 vs 55.6%, P  = 0.041). Low-dose anlotinib in combination with ICIs for advanced NSCLC may be an effective and well-tolerated option.

The aim of this study is to explore the role of the IL-10/STAT3 pathway in the upregulation of natural killer group 2, member D (NKG2D) ligands (MICA and ULBP2) induced by Bruton's tyrosine kinase (BTK) inhibitors in non-germinal center B-cell-like diffuse large B-cell lymphoma cells. The expression levels of NKG2D ligands and the IL-10/STAT3 pathway in SUDHL4, U2932, and OCI-LY3 cells were analyzed using western blotting. After stimulation of the B-cell receptor signaling pathway with IgM antibodies, the expression levels of NKG2D ligands, as well as IL-10 and phosphorylated STAT3 (p-STAT3) were significantly reduced. In contrast, treatment with ibrutinib produced effects opposite to those induced by IgM antibodies. Additionally, treatment of U2932 and OCI-LY3 cells with the STAT3 inhibitor (STAT3-IN-1) led to an increase in NKG2D ligand expression and a decrease in IL-10 levels. When IL-10 neutralizing antibodies were introduced, p-STAT3 levels decreased, and NKG2D ligand expression increased. Similar outcomes were observed when the BTK inhibitors ACP-196 and BGB-3111 were administered. Our findings suggest that the IL-10/STAT3 pathway plays a key role in the upregulation of NKG2D ligands induced by BTK inhibitors in U2932 and OCI-LY3 cells.

The objective of this study is to explore the effect of adjuvant chemotherapy with toad venom injection in patients with intermediate and advanced colon cancer, in order to provide new reference drugs for clinical treatment. Prospectively, 148 patients with mid-stage to late-stage colon cancer in our hospital from January 2021 to May 2023 were selected for the study and randomly divided into two groups of 74 cases each. The control group was treated with FOLFOX4 chemotherapy, and the observation group was treated with four consecutive chemotherapy cycles based on the control group combined with toad venom injection. The treatment effects, adverse reactions, quality of life improvement rate, prognosis and cellular immune indexes [natural killer (NK) cells, CD4+/CD8+, CD4+, CD3+], phosphatase tensin gene (PTEN), phosphatidylinositol-3-kinase (PI3k), and serine threonine protein kinase (pAKT) protein expression before and after treatment were counted in the two groups. The total effective rate of treatment in the observation group was 58.11% (43/74) after four cycles of chemotherapy, which was higher than that in the control group of 41.89% (31/74) (P < 0.05). After two cycles of chemotherapy and four cycles of chemotherapy, PTEN, CD4+/CD8+, CD4+, CD3+, and NK cells in peripheral blood were higher in the observation group than in the control group, and PI3k and pAKT were lower than in the control group (P < 0.05). There was no statistically significant difference in the rate of adverse reactions in the observation group compared with the control group (P > 0.05); the improvement rate of quality of life in the observation group was better than that in the control group after four chemotherapy cycles of treatment (P < 0.05); the survival rate was 75.00% (54/72) in the observation group compared with 54.29% (38/70) in the control group at 1-year follow-up. Toad venom injection adjuvant chemotherapy is effective in treating patients with intermediate and advanced colon cancer, which can upregulate PTEN level, inhibit PI3k and AKT expression, and improve immune function and quality of life of patients, thus improving prognosis.