Search Results (8)

We showed previously that the autocrine activation of the FGFR-mediated pathway in GIST lacking secondary KIT mutations was a result of the inhibition of KIT signaling. We show here that the FGF2/FGFR pathway regulates VEGF-A/VEGFR signaling in IM-resistant GIST cells. Indeed, recombinant FGF2 increased the production of VEGF-A by IM-naive and resistant GIST cells. VEGF-A production was also increased in KIT-inhibited GIST, whereas the neutralization of FGF2 by anti-FGF2 mAb attenuated VEGFR signaling. Of note, BGJ 398, pan FGFR inhibitor, effectively and time-dependently inhibited VEGFR signaling in IM-resistant GIST T-1R cells, thereby revealing the regulatory role of the FGFR pathway in VEGFR signaling for this particular GIST cell line. This also resulted in significant synergy between BGJ 398 and VEGFR inhibitors (i.e., sunitinib and regorafenib) by enhancing their pro-apoptotic and anti-proliferative activities. The high potency of the combined use of VEGFR and FGFR inhibitors in IM-resistant GISTs was revealed by the impressive synergy scores observed for regorafenib or sunitinib and BGJ 398. Moreover, FGFR1/2 and VEGFR1/2 were co-localized in IM-resistant GIST T-1R cells, and the direct interaction between the aforementioned RTKs was confirmed by co-immunoprecipitation. In contrast, IM-resistant GIST 430 cells expressed lower basal levels of FGF2 and VEGF-A. Despite the increased expression VEGFR1 and FGFR1/2 in GIST 430 cells, these RTKs were not co-localized and co-immunoprecipitated. Moreover, no synergy between FGFR and VEGFR inhibitors was observed for the IM-resistant GIST 430 cell line. Collectively, the dual targeting of FGFR and VEGFR pathways in IM-resistant GISTs is not limited to the synergistic anti-angiogenic treatment effects. The dual inhibition of FGFR and VEGFR pathways in IM-resistant GISTs potentiates the proapoptotic and anti-proliferative activities of the corresponding RTKi. Mechanistically, the FGF2-induced activation of the FGFR pathway turns on VEGFR signaling via the overproduction of VEGF-A, induces the interaction between FGFR1/2 and VEGFR1, and thereby renders cancer cells highly sensitive to the dual inhibition of the aforementioned RTKs. Thus, our data uncovers the novel mechanism of the cross-talk between the aforementioned RTKs in IM-resistant GISTs lacking secondary KIT mutations and suggests that the dual blockade of FGFR and VEGFR signaling might be an effective treatment strategy for patients with GIST-acquired IM resistance via KIT-independent mechanisms. Full article

Tumour-associated angiogenesis play key roles in tumour growth and cancer metastasis. Consequently, several anti-angiogenic drugs such as sunitinib and axitinib have been approved for use as anti-cancer therapies. However, the majority of these drugs target the vascular endothelial growth factor A (VEGFA)/VEGF receptor 2 (VEGFR2) pathway and have shown mixed outcome, largely due to development of resistances and increased tumour aggressiveness. In this study, we used the zebrafish model to screen for novel anti-angiogenic molecules from a library of compounds derived from natural products. From this, we identified canthin-6-one, an indole alkaloid, which inhibited zebrafish intersegmental vessel (ISV) and sub-intestinal vessel development. Further characterisation revealed that treatment of canthin-6-one reduced ISV endothelial cell number and inhibited proliferation of human umbilical vein endothelial cells (HUVECs), suggesting that canthin-6-one inhibits endothelial cell proliferation. Of note, canthin-6-one did not inhibit VEGFA-induced phosphorylation of VEGFR2 in HUVECs and downstream phosphorylation of extracellular signal-regulated kinase (Erk) in leading ISV endothelial cells in zebrafish, suggesting that canthin-6-one inhibits angiogenesis independent of the VEGFA/VEGFR2 pathway. Importantly, we found that canthin-6-one impairs tumour-associated angiogenesis in a zebrafish B16F10 melanoma cell xenograft model and synergises with VEGFR inhibitor sunitinib malate to inhibit developmental angiogenesis. In summary, we showed that canthin-6-one exhibits anti-angiogenic properties in both developmental and pathological contexts in zebrafish, independent of the VEGFA/VEGFR2 pathway and demonstrate that canthin-6-one may hold value for further development as a novel anti-angiogenic drug. Full article

Activated endothelial, immune, and cancer cells prefer glycolysis to obtain energy for their proliferation and migration. Therefore, the blocking of glycolysis can be a promising strategy against cancer and autoimmune disease progression. Inactivation of the glycolytic enzyme PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase) suppresses glycolysis level and contributes to decreased proliferation and migration of cancer (tumorigenesis) and endothelial (angiogenesis) cells. Recently, several glycolysis inhibitors have been developed, among them (E)-1-(pyridin-4-yl)-3-(quinolin-2-yl)prop-2-en-1-one (PFK15) that is considered as one of the most promising. It is known that PFK15 decreases glucose uptake into the endothelial cells and efficiently blocks pathological angiogenesis. However, no study has described sufficiently PFK15 synthesis enabling its general availability. In this paper we provide all necessary details for PFK15 preparation and its advanced characterization. On the other hand, there are known tyrosine kinase inhibitors (e.g., sunitinib), that affect additional molecular targets and efficiently block angiogenesis. From a biological point of view, we have studied and proved the synergistic inhibitory effect by simultaneous administration of glycolysis inhibitor PFK15 and multikinase inhibitor sunitinib on the proliferation and migration of HUVEC. Our results suggest that suppressing the glycolytic activity of endothelial cells in combination with growth factor receptor blocking can be a promising antiangiogenic treatment. Full article

A worldwide crisis with nitrosamine contamination in medical products began in 2018. Therefore, trace-level analysis of nitrosamines is becoming an emerging topic of interest in the field of quality control. A novel GC-MS method with electron ionization and microextraction was developed and validated for simultaneous determination of nine carcinogenic nitrosamines (NDMA, NMEA, NDEA, NDBA, NMOR, NPYR, NPIP, NDPA, and N-methyl-npz) in active pharmaceutical ingredients (APIs): cilostazol, sunitinib malate, and olmesartan medoxomil. The method was validated according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, demonstrating good linearity in the range of LOQ up to 21.6 ng/mL (120% of specification limit). The limits of detection for the nine nitrosamines were determined to be in the range 0.15–1.00 ng/mL. The developed trace level GC-MS method turned out to be specific, accurate, and precise. The accuracy of all the tested APIs ranged from 94.09% to 111.22% and the precision evaluated by repeatability, intermediate precision, and system precision was RSD ≤ 7.65%. Nitrosamines were not detected in cilostazol and sunitinib, whereas in olmesartan medoxomil NDEA was detected at the level of LOQ. The novel protocol was successfully applied for nitrosamines determination in selected APIs and can be used for the routine quality control of APIs under Good Manufacturing Practices rules, ensuring the safety and effectiveness of pharmaceutical products. Full article

In the current study, lipid-polymer hybrid nanoparticles (LPHNPs) fabricated with lipoid-90H and chitosan, sunitinib malate (SM), an anticancer drug was loaded using lecithin as a stabilizer by employing emulsion solvent evaporation technique. Four formulations (SLPN1–SLPN4) were developed by varying the concentration of chitosan polymer. Based on particle characterization, SLPN4 was optimized with size (439 ± 5.8 nm), PDI (0.269), ZP (+34 ± 5.3 mV), and EE (83.03 ± 4.9%). Further, the optimized formulation was characterized by FTIR, DSC, XRD, SEM, and in vitro release studies. In-vitro release of the drug from SPN4 was found to be 84.11 ± 2.54% as compared with pure drug SM 24.13 ± 2.67%; in 48 h, release kinetics followed the Korsmeyer–Peppas model with Fickian release mechanism. The SLPN4 exhibited a potent cytotoxicity against MCF-7 breast cancer, as evident by caspase 3, 9, and p53 activities. According to the findings, SM-loaded LPHNPs might be a promising therapy option for breast cancer. Full article

Age-related macular degeneration (AMD) will be responsible for the vision impairment of more than five million late-aged adults in the next 30 years. Current treatment includes frequent intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents. However, there are methods of drug delivery that can decrease the frequency of intravitreal injections by sustaining drug release. MPEG-PCL ((methoxypoly(ethylene glycol) poly(caprolactone)) has been reported as biocompatible and biodegradable. Polymeric micelles of MPEG-PCL can be useful in efficiently delivering anti-VEGF drugs such as sunitinib to the posterior segment of the eye. In this study, the novel micellar formulation exhibited an average dynamic light scattering (DLS) particle size of 134.2 ± 2.3 nm with a zeta potential of −0.159 ± 0.07 mV. TEM imaging further confirmed the nanoscopic size of the micelles. A sunitinib malate (SM)-MPEG-PCL formulation exhibited a sustained release profile for up to seven days with an overall release percentage of 95.56 ± 2.7%. In addition to their miniscule size, the SM-MPEG-PCL formulation showed minimal cytotoxicity onto the ARPE-19 human retinal pigment epithelial cell line, reporting a percent viability of more than 88% for all concentrations tested at time intervals of 24 h. The SM-MPEG-PCL micelles also exhibited exceptional performance during an anti-VEGF ELISA that decreased the overall VEGF protein expression in the cells across a 24–72 h period. Furthermore, it can be concluded that this type of polymeric vehicle is a promising solution to symptoms caused by AMD and improving the management of those suffering from AMD. Full article

A 55-year old man was treated with sunitinib 50 mg/day for 4 weeks on and 2 weeks off, as a first-line therapy for metastatic renal cell carcinoma. During the fourth week of the first cycle, he was admitted to the Emergency Department with abdominal pain and vomiting. Acute acalculous cholecystitis was diagnosed. Sunitnib-associated cholecystitis is a rare adverse event previously reported in few cases. The mechanism behind this complication is not fully understood, although vascular endothelial dysfunction may play a role. The use of this drug is expanding in clinical oncology, and physicians should be aware of this life-threating adverse event. Full article

Question: Is sunitinib malate—marketed as Sutent (Pfizer Canada, Kirkland, QC)—superior to placebo or other interventions for primary outcomes of interest in adult patients with gastrointestinal stromal tumour (GIST) who have developed resistance or who exhibit intolerance to imatinib mesylate (IM)? Background: In patients with resectable disease, surgery is the mainstay of treatment for GIST; in patients with unresectable or metastatic disease, the tyrosine kinase inhibitor IM is the therapy of choice. However, some patients have primary resistance or intolerance to IM, or they progress after optimal exposure (including an escalated dose). Here, we review the evidence for treating IM-resistant GIST with sunitinib malate. Methods: Studies of sunitinib malate were identified through MEDLINE, EMBASE, the Cochrane Library databases, and Web sites of guideline organizations. Outcomes of interest included time to progression, progression-free survival, overall survival, and toxicity. Results: One phase iii randomized controlled trial, and one abstract and presentation describing that trial, served as the evidentiary base for this clinical practice guideline. Trial data confidently show that both time to progression and progression-free survival are highly statistically significant (p < 0.0001) in favour of sunitinib malate over placebo. Overall survival was improved with sunitinib malate (hazard ratio: 0.49; 95% confidence interval: 0.29 to 0.83; p = 0.007; absolute difference in weeks not reported). The most frequent of all adverse effects (experienced in greater proportion by patients on sunitinib malate) were grades 1 and 2 leucopenia (52% vs. 5% with placebo), neutropenia (43% vs. 4%), and thrombocytopenia (36% vs. 4%). Grade 3 hematologic adverse events were also reported more frequently in the sunitinib malate group, including leucopenia (4% vs. 0%), neutropenia (8% vs. 4%), lymphopenia (9% vs. 2%), and thrombocytopenia (4% vs. 0%). Toxicity comparisons did not include p values. The incidence of grades 1–3 fatigue was greater for the sunitinib malate group (34% vs. 22% with placebo). Other grade 3 nonhematologic treatment-related adverse events that occurred more frequently on sunitinib malate included hand–foot syndrome (4% vs. 0%), diarrhea (3% vs. 0%), and hypertension (3% vs. 0%). No grade 4 adverse events were observed. Conclusions: In the target population, sunitinib malate is the recommended option for second-line therapy of metastatic GIST. Full article