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Journal of Biochemical and Molecular... Apr 2024Renal cell carcinoma (RCC) is the most common kidney cancer with high mortality rate. Pazopanib has been approved for the treatment of RCC. However, the underlying...
Renal cell carcinoma (RCC) is the most common kidney cancer with high mortality rate. Pazopanib has been approved for the treatment of RCC. However, the underlying mechanism is not clear. Here, we report a novel finding by showing that treatment with Pazopanib could promote cellular senescence of the human RCC cell line ACHN. Cells were stimulated with 5, 10, and 20 μM Pazopanib, respectively. Cellular senescence was measured using senescence-associated β-galactosidase (SA-β-Gal) staining. Western blot analysis and real-time polymerase chain reaction were used to measure the mRNA and protein expression of nuclear factor E2-related factor 2 (Nrf2), γH2AX, human telomerase reverse transcriptase (hTERT), telomeric repeat binding factor 2 (TERF2), p53 and plasminogen activator inhibitor (PAI). First, we found that exposure to Pazopanib reduced the cell viability of ACHN cells. Additionally, Pazopanib induced oxidative stress by increasing the production of reactive oxygen species, reducing the levels of glutathione peroxidase, and promoting nuclear translocation of Nrf2. Interestingly, Pazopanib exposure resulted in DNA damage by increasing the expression of γH2AX. Importantly, Pazopanib increased cellular senescence and reduced telomerase activity. Pazopanib also reduced the gene expression of hTERT but increased the gene expression of TERF2. Correspondingly, we found that Pazopanib increased the expression of p53 and PAI at both the mRNA and protein levels. To elucidate the underlying mechanism, the expression of Nrf2 was knocked down by transduction with Ad- Nrf2 shRNA. Results indicate that silencing of Nrf2 in ACHN cells abolished the effects of Pazopanib in stimulating cellular senescence and reducing telomerase activity. Consistently, knockdown of Nrf2 restored the expression of p53 and PAI in ACHN cells. Based on these results, we explored a novel mechanism whereby which Pazopanib displays a cytotoxicity effect in RCC cells through promoting cellular senescence mediated by Nrf2.
Topics: Humans; Carcinoma, Renal Cell; NF-E2-Related Factor 2; Telomerase; Tumor Suppressor Protein p53; Kidney Neoplasms; RNA, Messenger; Indazoles; Pyrimidines; Sulfonamides
PubMed: 38613465
DOI: 10.1002/jbt.23689 -
Cancer Reports (Hoboken, N.J.) Apr 2024NSCLC is a lethal cancer that is highly prevalent and accounts for 85% of cases of lung cancer. Conventional cancer treatments, such as chemotherapy and radiation,...
BACKGROUND
NSCLC is a lethal cancer that is highly prevalent and accounts for 85% of cases of lung cancer. Conventional cancer treatments, such as chemotherapy and radiation, frequently exhibit limited efficacy and notable adverse reactions. Therefore, a drug repurposing method is proposed for effective NSCLC treatment.
AIMS
This study aims to evaluate candidate drugs that are effective for NSCLC at the clinical level using a systems biology and network analysis approach.
METHODS
Differentially expressed genes in transcriptomics data were identified using the systems biology and network analysis approaches. A network of gene co-expression was developed with the aim of detecting two modules of gene co-expression. Following that, the Drug-Gene Interaction Database was used to find possible drugs that target important genes within two gene co-expression modules linked to non-small cell lung cancer (NSCLC). The use of Cytoscape facilitated the creation of a drug-gene interaction network. Finally, gene set enrichment analysis was done to validate candidate drugs.
RESULTS
Unlike previous research on repositioning drugs for NSCLC, which uses a gene co-expression network, this project is the first to research both gene co-expression and co-occurrence networks. And the co-occurrence network also accounts for differentially expressed genes in cancer cells and their adjacent normal cells. For effective management of non-small cell lung cancer (NSCLC), drugs that show higher gene regulation and gene affinity within the drug-gene interaction network are thought to be important. According to the discourse, NSCLC genes have a lot of control over medicines like vincristine, fluorouracil, methotrexate, clotrimazole, etoposide, tamoxifen, sorafenib, doxorubicin, and pazopanib.
CONCLUSION
Hence, there is a possibility of repurposing these drugs for the treatment of non-small-cell lung cancer.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Drug Repositioning; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks
PubMed: 38600056
DOI: 10.1002/cnr2.2031 -
Molecular and Clinical Oncology May 2024Elderberry flower extract is marketed as an herbal supplement with purported benefits in boosting the immune system. The use of elderberry increased during the...
Elderberry flower extract is marketed as an herbal supplement with purported benefits in boosting the immune system. The use of elderberry increased during the coronavirus pandemic. However, the interaction of elderberry with cytotoxic medicines has remained elusive. Pazopanib is a multikinase inhibitor approved for patients diagnosed with soft-tissue sarcoma. The present study reported on the case of a middle-aged woman diagnosed with localized intermediate-grade sarcoma of the left sartorius muscle who received neoadjuvant pazopanib with radiation therapy. The patient had no other medical comorbidities and only took over-the-counter (OTC) elderberry supplements for numerous years to 'boost' her immune system. She started pazopanib at 400 mg per os (PO) daily, which was increased to 800 mg PO daily after a week. By week three on pazopanib, the patient reported intense nausea and a number of loose stools, requiring anti-nausea medication. By the fourth week on pazopanib, laboratory tests showed grade 3 liver injury, as demonstrated by a fivefold rise in liver enzymes along with severe nausea and loose stools. All medications, including elderberry supplement, were stopped. Within two weeks of stopping all medicines, the liver enzymes started normalizing within two weeks and were normal by the end of four weeks. Pazopanib treatment was resumed without the recurrence of side effect. Pazopanib is metabolized in the liver via the cytochrome P 450 (CYP)3A4 enzyme pathway. Hence, potent inhibitors of CYP3A4 are avoided for concurrent use with pazopanib. Small studies on elderberry extracts have shown weak inhibition of CYP3A4. However, considering the wide usage of elderberry and the availability of mixed supplements OTC, it is essential to pursue clinical studies in cancer patients to understand the interactions of elderberry extracts with cytotoxic medicines. In this report, the scientific evidence behind the use of elderberry was reviewed and a hypothesis of its interaction with pazopanib was proposed.
PubMed: 38596626
DOI: 10.3892/mco.2024.2734 -
Translational Pediatrics Mar 2024Microphthalmia-associated transcription factor/transcription factor E (MiTF/TFE) translocation renal cell carcinoma (RCC) is a rare type of non-clear cell RCC (nccRCC),...
BACKGROUND
Microphthalmia-associated transcription factor/transcription factor E (MiTF/TFE) translocation renal cell carcinoma (RCC) is a rare type of non-clear cell RCC (nccRCC), which is more common in females. Currently, there is no standardized treatment for advanced metastatic microphthalmia translocation RCC (MiT-RCC). The main treatment modalities include surgery, chemotherapy, immunotherapy, anti-vascular endothelial growth factor or vascular endothelial growth factor receptor (VEGFR) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and targeted therapy against the mesenchymal-epithelial transition (MET) factor signaling pathway.
CASE DESCRIPTION
We present the case of an 8-year-old male patient with hematuria and paroxysmal urinary pain. Based on tumor genetic testing results and targeted drug matching analysis, the patient underwent tumor biopsy, tumor radical surgery with vascular osteotomy, and cervicothoracic lymph node dissection. The patient was then treated with a combination of immunotherapy [sintilimab, a drug directed against programmed cell death receptor-1 (PD-1)] and VEGFR tyrosine kinase inhibitor (TKI) (from pazopanib to sunitinib). Throughout the 10 cycles of conventional chemotherapy (seven courses of sintilimab since the start of the third chemotherapy treatment), the patient's condition remained stable, with no tumor recurrence at the primary site. However, in the later stages, the patient developed a large amount of ascites, and the family requested discontinuation of treatment, ultimately leading to the patient's death.
CONCLUSIONS
In this case report, we summarize the therapeutic strategy of a young patient with metastatic transcription factor E3 () MiT-RCC. For this disease, early immunotherapy and the use of precision-targeted drugs may have a favorable impact on the survival prognosis of the patient but may still be of less benefit in children with advanced multiple metastases. Therefore, further research on tumor driver genes, among other treatment components, is urgently needed to improve precision therapy.
PubMed: 38590368
DOI: 10.21037/tp-24-35 -
BioRxiv : the Preprint Server For... Mar 2024Hereditary Hemorrhagic Telangiectasia (HHT) is a rare congenital disease in which fragile vascular malformations focally develop in multiple organs. These can be small...
UNLABELLED
Hereditary Hemorrhagic Telangiectasia (HHT) is a rare congenital disease in which fragile vascular malformations focally develop in multiple organs. These can be small (telangiectasias) or large (arteriovenous malformations, AVMs) and may rupture leading to frequent, uncontrolled bleeding. There are few treatment options and no cure for HHT. Most HHT patients are heterozygous for loss-of-function mutations for Endoglin (ENG) or Alk1 (ACVRL1), however, why loss of these genes manifests as vascular malformations remains poorly understood. To complement ongoing work in animal models, we have developed a microphysiological system model of HHT. Based on our existing vessel-on-a-chip (VMO) platform, our fully human cell-based HHT-VMO recapitulates HHT patient vascular lesions. Using inducible (Alk1)-knockdown, we control timing and extent of endogenous Alk1 expression in primary human endothelial cells (EC) in the HHT-VMO. HHT-VMO vascular lesions develop over several days, and are dependent upon timing of Alk1 knockdown. Interestingly, in chimera experiments AVM-like lesions can be comprised of both Alk1-intact and Alk1-deficient EC, suggesting possible cell non-autonomous effects. Single cell RNA sequencing data are consistent with microvessel pruning/regression as contributing to AVM formation, while loss of PDGFB expression implicates mural cell recruitment. Finally, lesion formation is blocked by the VEGFR inhibitor pazopanib, mirroring the positive effects of this drug in patients. In summary, we have developed a novel HHT-on-a-chip model that faithfully reproduces HHT patient lesions and that is sensitive to a treatment effective in patients. The VMO-HHT can be used to better understand HHT disease biology and identify potential new HHT drugs.
SIGNIFICANCE
This manuscript describes development of an organ-on-a-chip model of Hereditary Hemorrhagic Telangiectasia (HHT), a rare genetic disease involving development of vascular malformations. Our VMO-HHT model produces vascular malformations similar to those seen in human HHT patients, including small (telangiectasias) and large (arteriovenous malformations) lesions. We show that VMO-HHT lesions are sensitive to a drug, pazopanib, that appears to be effective in HHT human patients. We further use the VMO-HHT platform to demonstrate that there is a critical window during vessel formation in which the HHT gene, Alk1, is required to prevent vascular malformation. Lastly, we show that lesions in the VMO-HHT model are comprised of both Alk1-deficient and Alk1-intact endothelial cells.
PubMed: 38559155
DOI: 10.1101/2024.03.11.584490 -
Clinical Genitourinary Cancer Jun 2024Inter-individual variability in drug response pose significant challenges to treatment with tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell... (Review)
Review
Inter-individual variability in drug response pose significant challenges to treatment with tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC). TKIs meet traditional criteria for using therapeutic drug monitoring (TDM), but research is still limited. Understanding the role of TDM in individualizing treatment strategies could help optimize treatment. Here we review the state of knowledge of TDM for TKIs in mRCC treatment. A comprehensive literature review of original research studies focusing on TDM of TKIs in mRCC treatment, clinical in vivo studies reporting on pharmacokinetics-pharmacodynamics, therapeutic ranges, drug concentrations, dose adjustments, clinical outcomes, or other relevant aspects related to TDM. We reviewed studies involving human subjects published in peer-reviewed journals. A narrative synthesis approach was employed to summarize the findings. Key themes and trends related to TDM of TKIs in mRCC treatment were identified and synthesized to provide a comprehensive overview of the current state of knowledge. Our search yielded 25 articles. Most were observational. The most consistently reported association between plasma concentration and effect was pazopanib Ctrough >20 µg/mL, but this concentration was not significant across all studies. We found inconsistent evidence for sunitinib and cabozantinib. For axitinib, we found a clear exposure-response relationship, but research was too diverse to conclude on a therapeutic window to use for TDM. We found much heterogeneity between recommended time of measurement (minimum plasma concentration [C], maximal plasma concentration [C], area under the curve [AUC]) and large variation in plasma concentration associated with clinical outcomes, which makes it difficult to recommend specific concentration intervals based on 1 or more of these measurements. Results were more consistent with TKIs continuously administered. Further research is needed to elucidate the long-term impact of TDM to possibly establish standardized therapeutic intervals. Prospective studies are suggested. The application of TDM in TKI-combination therapy is warranted in future research.
Topics: Humans; Carcinoma, Renal Cell; Drug Monitoring; Protein Kinase Inhibitors; Kidney Neoplasms; Indazoles; Sulfonamides; Pyrimidines; Antineoplastic Agents; Axitinib; Sunitinib; Treatment Outcome; Tyrosine Kinase Inhibitors
PubMed: 38555681
DOI: 10.1016/j.clgc.2024.102064 -
Journal of Cancer Research and... Jan 2024Treatment options for patients with metastatic sarcoma are limited. The goal of this study was to investigate the effectiveness of temozolomide in pretreated patients...
BACKGROUND
Treatment options for patients with metastatic sarcoma are limited. The goal of this study was to investigate the effectiveness of temozolomide in pretreated patients with soft tissue sarcoma.
METHODS
We recorded the pathological, clinical, and treatment data of the patients with metastatic soft tissue sarcoma retrospectively. We evaluated the efficacy and side effects of temozolomide in this patient group.
RESULTS
This study involved 16 patients. The average age was detected as 48 (21-73) years. Six (37.5%) patients had de-novo metastatic disease at diagnosis. Primary of tumors had originated from intra-abdominal (43.7%), extremity (31.3%), head-and-neck (12.5%), and intrathoracic (12.5%) regions. The patients previously had received at least two different chemotherapy regimens (75%), pazopanib (50%) and palliative radiotherapy (31.3%). Temozolomide-related median progression-free survival time was found as 3.5 (95% CI, 2.6-4.3) months. One patient (6.3%) had a partial response, while four patients (25%) had stable disease. Nine individuals (56.3%) had grade 1-2 adverse events, while one patient (6.3%) had grade 3-4 adverse events.
CONCLUSIONS
We observed that temozolomide was well tolerated but had limited efficacy in the treatment of metastatic sarcoma patients. In patients with extensively pretreated soft tissue sarcoma, temozolomide may be considered a therapeutic option as a single-agent.
Topics: Humans; Middle Aged; Aged; Temozolomide; Salvage Therapy; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms
PubMed: 38554304
DOI: 10.4103/jcrt.jcrt_1827_22 -
Translational Psychiatry Mar 2024Melatonin improves chronic stress-induced hippocampal damage and depression-like behaviors, but the mechanism needs further study. This study was to explore the...
Melatonin alleviates chronic stress-induced hippocampal microglia pyroptosis and subsequent depression-like behaviors by inhibiting Cathepsin B/NLRP3 signaling pathway in rats.
Melatonin improves chronic stress-induced hippocampal damage and depression-like behaviors, but the mechanism needs further study. This study was to explore the mechanism of melatonin inhibiting microglia pyroptosis. In virtro experiments, melatonin improved corticosterone-induced the ultrastructure and microstructure damage of HAPI cells by inhibiting pyroptosis, thereby increasing cell survival rate. Protein-protein interaction network and molecular autodocking predicted that Cathespin B might be the target of melatonin inhibition of NLRP3-mediated pyroptosis. Melatonin inhibited corticosterone-induced Cathespin B expression. Both Cathepsin B inhibitor CA-074Me and NLRP3 knockout inhibited the HAPI cells pyroptosis. Similarly, melatonin inhibited Cathepsin B agonist Pazopanib-induced activation of Cathepsin B/NLRP3 signaling pathway and HAPI cells pyroptosis. In vivo studies, melatonin inhibited chronic restraint stress (CRS)-induced activation of Cathepsin B/NLRP3 signaling pathway and alleviated hippocampal microglia pyroptosis in rats. Inhibition of microglia pyroptosis improved CRS-induced depression-like behaviors of rats. In addition, inhibition of Cathepsin B and NLRP3 alleviated hippocampal pyroptosis. Melatonin inhibited Pazopanib-induced activation of Cathepsin B/NLRP3 signaling pathway and hippocampal pyroptosis. These results demonstrated that melatonin could alleviate CRS-induced hippocampal microglia pyroptosis by inhibiting Cathepsin B/NLRP3 signaling pathway, thereby improving depression-like behaviors in rats. This study reveals the molecular mechanism of melatonin in the prevention and treatment of chronic stress-related encephalopathy.
Topics: Animals; Rats; Cathepsin B; Melatonin; Corticosterone; Depression; Microglia; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Signal Transduction; Hippocampus; Indazoles; Pyrimidines; Sulfonamides
PubMed: 38538614
DOI: 10.1038/s41398-024-02887-y -
Journal of Clinical Oncology : Official... Jun 2024Patients with no evidence of disease (NED) after metastasectomy for renal cell carcinoma are at high risk of recurrence. Pazopanib is an inhibitor of vascular... (Randomized Controlled Trial)
Randomized Controlled Trial
Randomized, Double-Blind Phase III Study of Pazopanib Versus Placebo in Patients With Metastatic Renal Cell Carcinoma Who Have No Evidence of Disease After Metastasectomy: ECOG-ACRIN E2810.
PURPOSE
Patients with no evidence of disease (NED) after metastasectomy for renal cell carcinoma are at high risk of recurrence. Pazopanib is an inhibitor of vascular endothelial growth factor receptor and other kinases that improves progression-free survival in patients with metastatic RCC (mRCC). We conducted a randomized, double-blind, placebo-controlled multicenter study to test whether pazopanib would improve disease-free survival (DFS) in patients with mRCC rendered NED after metastasectomy.
PATIENTS AND METHODS
Patients with NED after metastasectomy were randomly assigned 1:1 to receive pazopanib 800 mg once daily versus placebo for 52 weeks. The study was designed to observe an improvement in DFS from 25% to 45% with pazopanib at 3 years, corresponding to 42% reduction in the DFS event rate.
RESULTS
From August 2012 to July 2017, 129 patients were enrolled. The study was unblinded after 83 DFS events (92% information). The study did not meet its primary end point. An updated analysis at 60.5-month median follow-up from random assignment (95% CI, 59.3 to 71.0) showed that the 3-year DFS was 27.4% (95% CI, 17.9 to 41.7) for pazopanib and 21.9% (95% CI, 13.3 to 36.2) for placebo. Hazard ratio (HR) for DFS was 0.90 ([95% CI, 0.60 to 1.34]; = .29) in favor of pazopanib. Three-year overall survival (OS) was 81.9% (95% CI, 72.7 to 92.2) for pazopanib and 91.4% (95% CI, 84.4 to 98.9) for placebo. The HR for OS was 2.55 (95% CI, 1.23 to 5.27) in favor of placebo ( = .012). Health-related quality-of-life measures deteriorated in the pazopanib group during the treatment period.
CONCLUSION
Pazopanib did not improve DFS as the primary end point compared with blinded placebo in patients with mRCC with NED after metastasectomy. In addition, there was a concerning trend favoring placebo in OS.
Topics: Humans; Indazoles; Carcinoma, Renal Cell; Pyrimidines; Sulfonamides; Kidney Neoplasms; Double-Blind Method; Male; Female; Middle Aged; Aged; Metastasectomy; Adult; Angiogenesis Inhibitors; Disease-Free Survival; Aged, 80 and over
PubMed: 38531002
DOI: 10.1200/JCO.23.01544 -
Nature Reviews. Rheumatology May 2024
Topics: Pyrimidines; Indazoles; Sulfonamides; Humans; Osteoarthritis; Nanoparticles; Angiogenesis Inhibitors
PubMed: 38503892
DOI: 10.1038/s41584-024-01104-w