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Cancer Gene Therapy Jun 2022Extracellular vesicles (EVs) encompass a wide range of vesicles that are released by all cell types. They package protein, nucleic acids, metabolites, and other cargo...
Extracellular vesicles (EVs) encompass a wide range of vesicles that are released by all cell types. They package protein, nucleic acids, metabolites, and other cargo that can be delivered to recipient cells and affect their phenotypes. However, little is known about how pharmaceutical agents can alter EV secretion, protein and metabolic cargo, and the active biological processes taking place in these vesicles. In this study, we isolated EVs from human renal cell carcinoma (RCC) cells treated with tyrosine kinase inhibitors (TKIs) Sunitinib and Axitinib. We found these TKIs increase the number of large (lEVs) and small extracellular vesicles (sEVs) secreted from RCC cells in a dose-dependent manner. In addition, quantitative proteomics revealed that metabolic proteins are enriched in sEVs secreted from Sunitinib-treated cells. In particular, the glucose transporter GLUT1 was enriched in sEVs purified from TKI-treated cells. These sEVs displayed increased glucose uptake and glycolytic metabolism compared to sEVs released from vehicle-treated cells. Overexpression of GLUT1 in RCC cells augmented GLUT1 levels in sEVs, which subsequently displayed higher glucose uptake and glycolytic activity. Together, these findings suggest that these TKIs alter metabolic cargo and activity in RCC sEVs.
Topics: Axitinib; Carcinoma, Renal Cell; Extracellular Vesicles; Glucose; Glucose Transporter Type 1; Humans; Kidney Neoplasms; Sunitinib
PubMed: 34088993
DOI: 10.1038/s41417-021-00345-1 -
British Journal of Pharmacology Jul 2019Sunitinib is a small-molecule TK inhibitor associated with hepatotoxicity. The mechanisms of its toxicity are still unclear.
BACKGROUND AND PURPOSE
Sunitinib is a small-molecule TK inhibitor associated with hepatotoxicity. The mechanisms of its toxicity are still unclear.
EXPERIMENTAL APPROACH
In the present study, mice were treated with 60, 150, and 450 mg·kg sunitinib to evaluate sunitinib hepatotoxicity. Sunitinib metabolites and endogenous metabolites in liver, serum, faeces, and urine were analysed using ultra-performance LC electrospray ionization quadrupole time-of-flight MS-based metabolomics.
KEY RESULTS
Four reactive metabolites and impaired clearance of sunitinib in liver played a dominant role in sunitinib-induced hepatotoxicity. Using a non-targeted metabolomics approach, various metabolic pathways, including mitochondrial fatty acid β-oxidation (β-FAO), bile acids, lipids, amino acids, nucleotides, and tricarboxylic acid cycle intermediates, were disrupted after sunitinib treatment.
CONCLUSIONS AND IMPLICATIONS
These studies identified significant alterations in mitochondrial β-FAO and bile acid homeostasis. Activation of PPARα and inhibition of xenobiotic metabolism may be of value in attenuating sunitinib hepatotoxicity.
Topics: Animals; Antineoplastic Agents; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Fatty Acids; Feces; Liver; Male; Metabolic Diseases; Mice, Inbred C57BL; Protein Kinase Inhibitors; Sunitinib
PubMed: 30875096
DOI: 10.1111/bph.14664 -
Cirugia Y Cirujanos 2022Gastrointestinal Stromal Sarcomas (GIST) are mesenchymal neoplasms whose incidence accounts for 1-2% of digestive tumors, being located in the stomach (55-60%) and small... (Review)
Review
Gastrointestinal Stromal Sarcomas (GIST) are mesenchymal neoplasms whose incidence accounts for 1-2% of digestive tumors, being located in the stomach (55-60%) and small intestine (30%). The advances in its knowledge and management succeeded in the last years have being spectacular. This review aims to summarize the most important of them for surgeons. We identified four areas of interest: molecular oncology, laparoscopic approach, management of GIST located at unusual locations, and management of advanced GIST. Advances in the field of molecular oncology lead to the discovery of new oncogenic mutations making the term Wil Type GIST obsolete. Moreover, these advances allow for the development of 2 new drugs: Avapritinib and Ripretinib, that added to the previous 3 commercially available drugs (imatinib, sunitinib and regorafenib) make possible the management of GIST with resistant mutations. The principles of the surgical management of primary GIST are well stablished which laparoscopic approach must accomplish. This approach is limited by 2 main factors: location and size. The diagnosis of GIST in unusual locations as esophagus, duodenum, rectum of out of the gastrointestinal tract (EGIST), implies an extraordinary therapeutic challenge, being imperative to manage them by surgeons and oncologist among others in the setting of a multidisciplinary team. The management of advanced/metastatic GIST has changed in a revolutionary fashion because surgery is now part of its treatment as adjuvant to tyrosine kinase inhibitors.
Topics: Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Sunitinib
PubMed: 35350056
DOI: 10.24875/CIRU.20001318 -
International Journal of Oral Science Dec 2023Recent studies have suggested that long-term application of anti-angiogenic drugs may impair oral mucosal wound healing. This study investigated the effect of sunitinib...
Recent studies have suggested that long-term application of anti-angiogenic drugs may impair oral mucosal wound healing. This study investigated the effect of sunitinib on oral mucosal healing impairment in mice and the therapeutic potential of Bifidobacterium breve (B. breve). A mouse hard palate mucosal defect model was used to investigate the influence of sunitinib and/or zoledronate on wound healing. The volume and density of the bone under the mucosal defect were assessed by micro-computed tomography (micro-CT). Inflammatory factors were detected by protein microarray analysis and enzyme-linked immunosorbent assay (ELISA). The senescence and biological functions were tested in oral mucosal stem cells (OMSCs) treated with sunitinib. Ligated loop experiments were used to investigate the effect of oral B. breve. Neutralizing antibody for interleukin-10 (IL-10) was used to prove the critical role of IL-10 in the pro-healing process derived from B. breve. Results showed that sunitinib caused oral mucosal wound healing impairment in mice. In vitro, sunitinib induced cellular senescence in OMSCs and affected biological functions such as proliferation, migration, and differentiation. Oral administration of B. breve reduced oral mucosal inflammation and promoted wound healing via intestinal dendritic cells (DCs)-derived IL-10. IL-10 reversed cellular senescence caused by sunitinib in OMSCs, and IL-10 neutralizing antibody blocked the ameliorative effect of B. breve on oral mucosal wound healing under sunitinib treatment conditions. In conclusion, sunitinib induces cellular senescence in OMSCs and causes oral mucosal wound healing impairment and oral administration of B. breve could improve wound healing impairment via intestinal DCs-derived IL-10.
Topics: Animals; Mice; Interleukin-10; Bifidobacterium breve; Up-Regulation; Angiogenesis Inhibitors; Sunitinib; X-Ray Microtomography; Administration, Oral; Wound Healing; Antibodies, Neutralizing
PubMed: 38072973
DOI: 10.1038/s41368-023-00263-y -
Cancer Medicine Mar 2023The phase 3 CLEAR study demonstrated statistically significantly improved efficacy with lenvatinib plus pembrolizumab versus sunitinib, including progression-free... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The phase 3 CLEAR study demonstrated statistically significantly improved efficacy with lenvatinib plus pembrolizumab versus sunitinib, including progression-free survival and overall survival, in patients with previously untreated advanced renal cell carcinoma. This subset analysis investigated efficacy and safety in Japanese patients randomized to lenvatinib plus pembrolizumab or sunitinib in the CLEAR study.
METHODS
Progression-free survival, overall survival, tumor response, and safety were assessed in Japanese patients with previously untreated advanced renal cell carcinoma randomized to receive lenvatinib plus pembrolizumab (n = 42) or sunitinib (n = 31). Efficacy outcomes were analyzed by independent imaging review per Response Evaluation Criteria in Solid Tumors, version 1.1.
RESULTS
Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 22.1 vs. 10.9 months; hazard ratio, 0.39; 95% CI, 0.20-0.74). Median overall survival was not estimable in the lenvatinib plus pembrolizumab arm and 30.6 months in the sunitinib arm (HR, 1.20; 95% CI, 0.39-3.66). Overall survival adjusted for the imbalance of Memorial Sloan-Kettering Cancer Center prognostic risk group favored lenvatinib plus pembrolizumab (hazard ratio, 0.67; 95% CI, 0.18-2.39). Objective response rate (69.0% vs. 45.2%; odds ratio, 2.71; 95% CI, 1.03-7.10) was higher and median duration of response (20.3 vs. 9.1 months) was longer with lenvatinib plus pembrolizumab versus sunitinib. Grade ≥ 3 treatment-emergent adverse events occurred in 95.2% versus 87.1% of patients in the lenvatinib plus pembrolizumab versus sunitinib arms.
CONCLUSIONS
These findings support lenvatinib plus pembrolizumab as a potential first-line treatment for Japanese patients with advanced renal cell carcinoma.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; East Asian People; Kidney Neoplasms; Sunitinib
PubMed: 36457273
DOI: 10.1002/cam4.5483 -
Journal of B.U.ON. : Official Journal... 2019The treatment of metastatic clear-cell renal cell cancer (mccRCC) has seen substantial progress over the last decade. Until 2006, non-specific immunotherapy with high... (Review)
Review
The treatment of metastatic clear-cell renal cell cancer (mccRCC) has seen substantial progress over the last decade. Until 2006, non-specific immunotherapy with high dose interleukin-2 (HD IL-2) was considered as standard therapy of mccRCC. The transition from cytokine to targeted therapy, and now to novel immunotherapeutic agents, significantly increased the overall survival (OS) of patients with mccRCC. Currently, 7 targeted agents and the combination of nivolumab/ipilimumab (immune checkpoint inhibitors, ICIs) have been approved as first-line therapy for mccRCC. Based on evidence from randomized phase III clinical trials, sunitinib and pazopanib (Tyrosine kinase inhibitors of vascular endothelial growth factor; VEGF-TKIs) are the most effective first-line options, especially in favorable and indermediate risk patients. Nivolumab/ipilimumab (dual checkpoint inhibitors) seem to be the preferred first-line therapy in poor-risk patients, although cabozantinib, temsirolimus, sunitinib and pazopanib are also recommended. HD IL-2 remains a reasonable first-line treatment option in selected, favorable-risk younger patients with good performance status. Based on data of previous phase I and II studies, several phase III trials investigating the efficacy and safety of the combination of ICI/VEGF-TKI versus sunitinib in untreated mccRCC are currently underway. These emerging therapies include the combinations of pembrolizumab/lenvatinib, pembrolizumab/axitinib, avelumab/axitinib and atezolizumab/ bevacizu-mab and seem to introduce the mccRCC therapy in a new auspicious era. Moreover, emerging new targeted therapies and other, beyond ICIs, immunotherapies are currently underway.
Topics: Antibodies, Monoclonal, Humanized; Carcinoma, Renal Cell; Combined Modality Therapy; Humans; Immunotherapy; Interleukin-2; Neoplasm Metastasis; Nivolumab; Progression-Free Survival; Sunitinib
PubMed: 31646776
DOI: No ID Found -
Cancer Medicine Jun 2023Imatinib is the standard first-line treatment for advanced gastrointestinal stromal tumors (GISTs); however, most patients eventually develop imatinib resistance,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Imatinib is the standard first-line treatment for advanced gastrointestinal stromal tumors (GISTs); however, most patients eventually develop imatinib resistance, leading to considerable clinical challenges. Few direct comparisons have been made between different post-first-line therapies on clinical efficacy in advanced GIST following imatinib failure.
METHODS
Databases including PubMed, Embase, Scopus, Google Scholars, and Cochrane Library from inception to February 2023 were retrieved for randomized controlled trials evaluating the clinical efficacy of different post-first-line agents for advanced GIST following imatinib failure. Network and conventional meta-analysis were carried out using Stata/MP 16.0.
RESULTS
Ripretinib showed significant improvement in progression-free survival (PFS) rates from the 2nd to the 12th month compared to placebo, while there was virtually no evidence that the rest active agents had a significant benefit at the 12th month. Masitinib, ripretinib, sunitinib, regorafenib, and pimitespib exhibited significantly longer median PFS than placebo, and pairwise comparisons indicated there were no significant differences among masitinib, ripretinib, and sunitinib. These post-first-line agents decreased the risk of disease progression or death by 65% (HR = 0.35, 95% CI: 0.26-0.47) compared to placebo. Ripretinib and sunitinib came into effect earlier and exhibited more consistent overall survival (OS) rate improvements than masitinib and pimitespib, while pairwise comparisons revealed no significant differences in these four active agents concerning the improvement in OS rate. These post-first-line agents decreased the risk of death by 39% (HR = 0.61, 95% CI: 0.44-0.83) over placebo for advanced GIST following imatinib failure.
CONCLUSION
The active agents in our analysis as post-first-line therapies are able to provide superior clinical efficacy, with improved PFS rate and OS rate at certain time points, as well as absolute values of PFS and OS for advanced GIST. Ripretinib might be the optimal recommendation as a post-first-line treatment for advanced GIST following imatinib failure.
Topics: Humans; Imatinib Mesylate; Gastrointestinal Stromal Tumors; Sunitinib; Network Meta-Analysis; Gastrointestinal Neoplasms; Indoles; Pyrroles; Antineoplastic Agents; Protein Kinase Inhibitors
PubMed: 37084005
DOI: 10.1002/cam4.5912 -
International Journal of Molecular... Jun 2021Resistance in clear cell renal cell carcinoma (ccRCC) against sunitinib is a multifaceted process encompassing numerous molecular aberrations. This induces clinical...
Resistance in clear cell renal cell carcinoma (ccRCC) against sunitinib is a multifaceted process encompassing numerous molecular aberrations. This induces clinical complications, reducing the treatment success. Understanding these aberrations helps us to select an adapted treatment strategy that surpasses resistance mechanisms, reverting the treatment insensitivity. In this regard, we investigated the dominant mechanisms of resistance to sunitinib and validated an optimized multidrug combination to overcome this resistance. Human ccRCC cells were exposed to single or chronic treatment with sunitinib to obtain three resistant clones. Upon manifestation of sunitinib resistance, morphometric changes in the cells were observed. At the molecular level, the production of cell membrane and extracellular matrix components, chemotaxis, and cell cycle progression were dysregulated. Molecules enforcing the cell cycle progression, i.e., cyclin A, B1, and E, were upregulated. Mass spectrometry analysis revealed the intra- and extracellular presence of -desethyl sunitinib, the active metabolite. Lysosomal sequestration of sunitinib was confirmed. After treatment with a synergistic optimized drug combination, the cell metabolic activity in Caki-1-sunitinib-resistant cells and 3D heterotypic co-cultures was reduced by >80%, remaining inactive in non-cancerous cells. These results demonstrate geno- and phenotypic changes in response to sunitinib treatment upon resistance induction. Mimicking resistance in the laboratory served as a platform to study drug responses.
Topics: Antineoplastic Agents; Biomarkers; Carcinoma, Renal Cell; Cell Cycle; Cell Line, Tumor; Drug Resistance, Neoplasm; Fluorescent Antibody Technique; Gene Expression; Gene Expression Profiling; Humans; Kidney Neoplasms; Models, Biological; Protein Kinase Inhibitors; Sunitinib
PubMed: 34208775
DOI: 10.3390/ijms22126467 -
International Journal of Molecular... Sep 2019This paper reviews current treatments for renal cell carcinoma/cancer (RCC) with the multikinase inhibitors (MKIs) sorafenib, sunitinib, lenvatinib and axitinib.... (Review)
Review
This paper reviews current treatments for renal cell carcinoma/cancer (RCC) with the multikinase inhibitors (MKIs) sorafenib, sunitinib, lenvatinib and axitinib. Furthermore, it compares these drugs regarding progression-free survival, overall survival and adverse effects (AE), with a focus on hypertension. Sorafenib and sunitinib, which are included in international clinical guidelines as first- and second-line therapy in metastatic RCC, are now being challenged by new-generation drugs like lenvatinib and axitinib. These drugs have shown significant clinical benefits for patients with RCC, but all four induce a variety of AEs. Hypertension is one of the most common AEs related to MKI treatment. Comparing sorafenib, sunitinib and lenvatinib revealed that sorafenib and sunitinib had the same efficacy, but sorafenib was safer to use. Lenvatinib showed better efficacy than sorafenib but worse safety. No trials have yet been completed that compare lenvatinib with sunitinib. Although axitinib promotes slightly higher hypertension rates compared to sunitinib, the overall discontinuation rate and cardiovascular complications are favourable. Although the mean rate of patients who develop hypertension is similar for each drug, some trials have shown large differences, which could indicate that lifestyle and/or genetic factors play an additional role.
Topics: Axitinib; Carcinoma, Renal Cell; Humans; Hypertension; Kidney Neoplasms; Phenylurea Compounds; Quinolines; Sorafenib; Sunitinib
PubMed: 31547602
DOI: 10.3390/ijms20194712 -
Analytical Cellular Pathology... 2022Endometriosis (EMs) is one of the most common gynecological diseases, lacking effective treatment. EMs are currently being treated with small molecule targeted therapy,...
Endometriosis (EMs) is one of the most common gynecological diseases, lacking effective treatment. EMs are currently being treated with small molecule targeted therapy, which has resulted in a significant reduction in patient suffering. Our previous studies have shown that sunitinib plays an obvious role in migration. Consequently, the purpose of this study is to explore the molecular mechanism by which sunitinib suppressed the ectopic endometrial migration. The ectopic endometrial cells from patients were divided into two groups: the control group and the sunitinib group. Co-IP and protein spectrum assay were employed to filtrate differential proteins between two groups, and then, our study discovered a signaling pathway, p-VEGFR-PI3K-AKT-YBX1-Snail, in the cell of EMs. To confirm this signaling pathway, VEGF165 was added to the sunitinib group to upregulate the expression of VEGFR. Next, the expression of p-VEGFR, PI3K, AKT, YBX1, and snail was measured in the control group and sunitinib group (compared with the control group: p-VEGFR, PI3K, AKT, YBX1, and snail, ∗∗∗∗ < 0.0001) and the VEGFR+sunitinib group (compared with the sunitinib group: p-VEGFR, PI3K, AKT, and snail, ∗∗∗∗ < 0.0001; YBX1, ∗∗∗ < 0.001); finally, the outcome was as expected. In addition to in vitro experiments, we also conducted in vivo experiments in mice. In the EMs mouse model, we found sunitinib reduced the number of heterotopic foci ( = 11.16, ∗∗∗∗ < 0.0001) and inhibited the expression of p-VEGFR, YBX1, and snail by immunofluorescence. To sum up, sunitinib exactly reduced the migration of ectopic endometrial cells with the involvement of the p-VEGFR-PI3K-AKT-YBX1-Snail signaling pathway in both in vitro and in vivo experiments. This study suggests that sunitinib presents a potential targeted drug for EMs therapy.
Topics: Animals; Cell Movement; Cell Proliferation; Female; Mice; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Sunitinib
PubMed: 35837295
DOI: 10.1155/2022/6042518