Anti-Cancer Drugs最新文献

Paclitaxel-induced peripheral neuropathy (PN) is a significant clinical concern for which no approved treatment is currently available. The purpose of this trial was to investigate the neuro-prophylactic impact of pentoxifylline against paclitaxel-induced PN in patients diagnosed with breast cancer (BC). BC patients who were assigned to paclitaxel chemotherapy were randomly allocated to pentoxifylline or a control group for 12 weeks. The main outcomes included the assessment of PN incidence according to the defined Common Terminology Criteria for Adverse Events, quality of life (QoL) using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTx) scale, and neuropathic pain using the scale of self-reported Leeds Assessment for Neuropathic Symptoms and Signs (s-LANSS). The code of the clinical trial registration is NCT06562998. The current study included a total of 72 patients allocated into pentoxifylline arm ( n  = 35) and placebo arm ( n  = 37). By the 12 th week, the prevalence of PN (grade 2 or 3) was significantly lower in the pentoxifylline arm 10/35 (28.6%) compared to 24/37 (64.9%) of the controls ( P value = 0.016). The total FACT/GOG-NTx score indicated a considerably worse QoL in the control group [98.18 (10.2) vs. 81.43 (14.8) for pentoxifylline and the control group, respectively, P < 0.001] with a mean difference of -16.75 [95% confidence interval (CI): -23.97 to -9.53]. S-LANSS scale showed significantly higher scores after 6 weeks [13.72 (5.86) vs. 17.52 (3.16), P  = 0.002] and 12 weeks [17.84 (4.25) vs. 23.80 (1.00), P  < 0.001] for pentoxifylline and control group, respectively. In conclusion, the use of pentoxifylline showed a significant reduction in paclitaxel-induced PN, which improved their QoL.

Small cell lung cancer (SCLC) constitutes around 15% of lung cancer cases and stands as the primary cause of cancer-related fatalities in men and the second leading cause in women globally. In this study, our objective was to evaluate the levels of C-reactive protein (CRP) and procalcitonin (PCT) in newly diagnosed extensive-stage SCLC patients without evidence of infection. We aimed to demonstrate that elevated CRP and PCT levels may not solely indicate infection but could also be elevated in malignancies. Furthermore, we sought to correlate these marker levels with patient and disease characteristics to elucidate the relationship between these inflammation markers and disease progression. A total of 115 patients who were pathologically and radiologically diagnosed with extensive-stage SCLC between January 2020 and December 2022 and who had received no prior treatment were included in the study. The Kaplan-Meier analysis revealed a median progression-free survival (PFS) of 7.46 months [95% confidence interval (CI), 6.85-8.07] and a median overall survival (OS) of 10.50 months (95% CI, 8.69-12.30) for all patients. In the group with elevated PCT, the median PFS was 6.73 months (95% CI, 3.92-9.54), whereas it was 7.86 months (95% CI, 7.13-8.59) in the group with normal PCT ( P  = 0.002). Similarly, the median OS was 9.10 months (95% CI, 5.61-12.58) in the elevated PCT group and 11.66 months (95% CI, 9.59-13.74) in the normal PCT group ( P  = 0.006). Patients with elevated procalcitonin (PRC) levels at the time of diagnosis exhibited shorter PFS and OS durations compared to patients with normal PRC levels. Furthermore, elevated CRP has also been demonstrated to correlate with poorer prognosis in extensive-stage SCLC.

We aimed to explore the role of ikarugamycin (IKA) in breast cancer, its connection with hexokinase-2 (HK-2) repression, and tissue factor (TF). This study sought to extend the role of HK-2 as a TF activator in a comprehensive analysis of these interactions from the enzyme, gene, and protein levels. The investigation was performed with MDA-MB-231 and MCF-7 breast cancer lines. The oxidative stress index (OSI), lactate production, and HK activity were assessed using colorimetric assays. Western blot and quantitative PCR analyses were performed to determine HK-2 and TF expressions. Prothrombin time Tests additionally assessed the effect of IKA therapy on TF activation. Three over four significantly downregulated genes were identified after a specific analysis of the IKA's effect on HK-2 and TF in breast cancer cell lines. In the IKA treatment group, lactate production was markedly reduced (P < 0.05) and hexokinase activity was found to be reduced in all groups (P < 0.05, <0.01). Paclitaxel cytotoxicity independently causes lower OSI in all IKA-treated groups as compared to controls even though OSI is elevated in IKA groups compared to control. Molecular analysis results demonstrated significantly downregulated HK-2 and TF expressions at the protein level (P < 0.05, P < 0.01). Partial thromboplastin time results also showed that IKA-treated cells had longer TF activation duration. A potential indirect association of HK-2 inhibition and TF regulation in breast cancer cells is put forward in this study by presenting IKA's bioactivation of breast cancer in all gene, protein, and enzyme levels.

Anlotinib, a tyrosine kinase inhibitor, has shown encouraging antitumor activity in platinum-resistant/refractory ovarian cancer. The efficacy of anlotinib as maintenance therapy in advanced ovarian cancer remains unclear. Therefore, we designed this study to evaluate the efficacy and safety of anlotinib maintenance therapy following first-line treatment with paclitaxel and platinum-based chemotherapy in advanced ovarian cancer. In this single-arm, phase II clinical trial, patients with newly diagnosed advanced ovarian cancer were received anlotinib monotherapy as maintenance therapy once after a response to platinum-based chemotherapy until tumor progression or intolerable toxicity. The primary endpoint was progression-free survival. From April 2020 to June 2021, 24 patients were enrolled in this study. The median follow-up was 40.17 months (interquartile range, 32.40-47.93 months). Of 21 patients with efficacy value, the median progression-free survival and median overall survival were 15.8 months (95% confidence interval, 6.8-24.8 months) and 43.8 months (95% confidence interval, 25.45-62.15 months). The quality-adjusted progression-free survival was 14.4 months and there were no observed treatment-related deaths or serious treatment-emergent adverse events, demonstrating the safety of anlotinib in maintenance therapy. Anlotinib shows significant potential as a first-line maintenance therapy for advanced ovarian cancer, extending survival and providing a reliable treatment option.

In gastric cancer, the relationship between human epidermal growth factor receptor 2 (HER2), the cyclic GMP-AMP synthase-stimulator of the interferon genes (cGAS-STING) pathway, and autophagy remains unclear. This study examines whether HER2 regulates autophagy in gastric cancer cells via the cGAS-STING signaling pathway, influencing key processes such as cell proliferation and migration. Understanding this relationship could uncover new molecular targets for diagnosis and treatment. Through lentiviral transfection, cell counting kit-8 assays, colony formation, transwell migration, scratch assays, and siRNA, we found that HER2 overexpression suppresses the cGAS-STING pathway, inhibits autophagy, and enhances the migratory ability of gastric cancer cells. In contrast, HER2 knockdown activates the cGAS-STING pathway, promotes autophagy, and reduces cell migration. We further observed that the inhibition of autophagy using chloroquine (CQ) increases the migration ability of HER2-overexpressing cells. Moreover, interfering with STING expression reversed the migration defects caused by HER2 knockdown, underscoring the critical role of the cGAS-STING pathway in HER2-regulated cell migration. We also revealed that high STING expression in gastric cancer is significantly associated with poor prognosis. STING expression was identified as an independent prognostic factor for survival (hazard ratio, 1.942; 95% confidence interval, 1.06-3.54; P = 0.031). These results highlight the importance of HER2-driven regulation of autophagy through the cGAS-STING pathway in gastric cancer progression and its potential as a therapeutic target.

Uncommon atypical mutations account for 10-15% of all epidermal growth factor receptor (EGFR) activating mutations in nonsmall-cell lung cancer (NSCLC). Tumors harboring rare EGFR mutations show highly heterogeneous responses to EGFR tyrosine kinase inhibitors (TKIs). There is insufficient clinical evidence for uncommon types of EGFR mutations, especially those with compound EGFR mutations. In addition, for those with uncommon compound EGFR mutations, few studies have focused on acquired resistance mechanisms and subsequent treatment strategies after disease progression on EGFR-TKIs. Here, a 66-year-old smoking male was diagnosed with lung adenocarcinoma accompanied by pleural metastasis. A rare L833V/H835L compound mutation in exon 21 of EGFR was detected in tumor biopsy by next-generation sequencing. Afatinib was used as first-line therapy and showed favorable efficacy. The patient continued afatinib treatment for a duration of 24 months. A new T790M mutation was detected with a rebiopsy after progression on afatinib. Then the patient received cryoablation therapy and a third-generation EGFR-TKI, furmonertinib. Our case suggests that a comprehensive screening for EGFR mutations should be conducted before and during treatment in clinical practice, and afatinib and furmonertinib could be first- and second-line treatment options in NSCLC patients harboring EGFR L833V/H835L mutations.

Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer with limited therapeutic options and poor prognosis. In this study, we explored the therapeutic potential of BGJ398, a selective fibroblast growth factor receptor (FGFR) inhibitor, alone and in combination with standard chemotherapy (cisplatin and paclitaxel) in SCLC. High-throughput screening of kinase inhibitors was performed on three SCLC cell lines (NCI-H446, NCI-H69, and NCI-H182), identifying BGJ398 as one of the most potent and selective inhibitors. BGJ398 demonstrated significant synergy with cisplatin and paclitaxel in vitro, as indicated by combination index values below 1. In vivo, combination treatments significantly inhibited tumor growth and extended survival in SCLC xenograft models compared to monotherapies. Notably, the combination of BGJ398 with cisplatin exhibited the most pronounced tumor suppression and survival benefits. Immunohistochemistry analysis confirmed that BGJ398 effectively inhibited FGFR signaling pathways, reducing levels of phosphorylated FGFR, protein kinase B, signal transducer and activator of transcription 3, and extracellular signal-regulated kinase. These findings suggest that BGJ398, particularly in combination with chemotherapy, holds significant promise as a treatment strategy for SCLC, providing enhanced anti-tumor efficacy and improved survival outcomes.

Recent studies have shown that Janus Kinase inhibitors can enhance the tumor therapeutic effect of immune checkpoint inhibitors. However, it remains to be studied whether TYK2 selective inhibitors can enhance the therapeutic effect of small molecule PD-L1 inhibitors in triple-negative breast cancer (TNBC). We verified the efficacy of the combination of the selective TYK2 inhibitor Deucravacitinib and the small molecule inhibitor of PD-L1, INCB086550, in two TNBC animal models: a syngeneic mouse model (4T1 with humanized PD-L1) and a peripheral blood mononuclear cell (PBMC)-humanized model (MDA-MB-231). Following that, we explored the regulation of immune cell activity in tumors by the combined treatment using flow cytometry. Finally, we validated the expression of genes related to the regulated immune cells through reverse transcription-PCR. Both animal models demonstrated that the addition of a TYK2 inhibitor to a PD-L1 inhibitor significantly enhanced the antitumor capabilities of mice with good safety profiles. The combined therapy significantly elevated the counts of T, B, and natural killer cells while concurrently diminishing myeloid-derived suppressor cells in the syngeneic model. Similarly, in the PBMC-humanized model, this therapy markedly augmented progenitor-like and proliferative precursor-like CD8 T cells, while effectively diminishing exhausted and terminally differentiated CD8 T cell populations. This enhanced antitumor effect is associated with the modulation of antitumor immune-related gene expression by the combined therapy. The combination of TYK2 inhibitors and immune checkpoint inhibitors is a potentially effective strategy for treating TNBC.

The uncertain ferroptosis-related role of berberine in prostate cancer was explored using network pharmacology methodology. Integration of ferroptosis targets in prostate cancer from the Genecard database and berberine targets from the Traditional Chinese Medicine Systems Pharmacology and SwissTargetPrediction databases revealed 17 common targets. Among these, 10 hub genes, including CCNB1, CDK1, AURKA, AR, CDC42, ICAM1, TYMS, NTRK1, PTGS2, and SCD, were identified. Enrichment analyses yielded 799 Gene Ontology terms and 23 Kyoto Encyclopedia of Genes and Genomes pathways associated with berberine-related targets. Molecular docking simulations indicated berberine's binding capacity to all hub genes. In-vitro studies on LNCaP and PC3 cells demonstrated berberine's inhibition of cell proliferation and significant downregulation of TYMS, CCNB1, AURKA, CDK1, and SCD in both cell lines. Berberine exhibited cell line-specific effects by reducing AR expression in LNCaP cells and suppressing ICAM1 in PC3 cells. Overall, berberine shows promise in inhibiting prostate cancer progression through modulation of ferroptosis-related genes, including TYMS, AR, CCNB1, AURKA, CDK1, ICAM1, NTRK1, SCD, and CDC42.

This study aimed to evaluate the efficacy of pyrotinib, an orally administered small molecule tyrosine kinase inhibitor, combined with neoadjuvant chemotherapy in treating patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Pyrotinib works by inhibiting the HER2 signaling pathway, thereby preventing tumor cell growth. This single-arm clinical trial aimed to assess the total pathological complete response (tpCR; ypT0/is and ypN0) rate as the primary endpoint. A total of 27 patients were enrolled, each receiving 4-8 cycles of pyrotinib in combination with neoadjuvant chemotherapy. Pyrotinib combined with neoadjuvant chemotherapy demonstrated notable antitumor activity in patients with HER2-positive breast cancer. Among 26 patients, the tpCR rate was 26% (7/26), while the breast pathological complete response rate was 30% (8/26), indicating complete inhibition of the primary tumor in some cases. Notably, patients with HR-negative breast cancer demonstrated a higher tpCR rate compared with those with HR-positive breast cancer. The treatment regimen was well-tolerated. Diarrhea was the most common adverse event, occurring in 92.3% of patients, with 46.2% experiencing grade 3 or higher diarrhea. No severe adverse events or treatment-related fatalities were reported.