Tyrosine kinase inhibitors (TKIs) are highly effective in treating chronic myelogenous leukemia (CML). However, primary and acquired drug resistance to TKIs have been reported. In this study, we used RNA sequencing followed by RQ-PCR to show that the proto-oncogene EVI1 targets the drug-metabolizing gene PTGS1 in CML. The PTGS1 promoter element had an EVI1 binding site, and CHIP assay confirmed its presence. Data from a publicly available CML microarray dataset and an independent set of CML samples showed a significant positive correlation between EVI1 and PTGS1 expression in CML. Downregulation of EVI1 in K562 cells and subsequent treatment with TKIs resulted in a lower IC₅₀ in the control cells. Furthermore, combined inhibition of BCR-ABL with imatinib and PTGS1 with FR122047 (PTGS1 inhibitor) synergistically reduced the viability of imatinib-resistant K562 cells. We conclude that elevated EVI1 expression contributes to TKIs resistance and that combined inhibition of PTGS1 and BCR-ABL may represent a novel therapeutic approach.

01 Aug 2020·Basic & Clinical Pharmacology & Toxicology

A sex‐specific, COX‐derived/thromboxane receptor activator causes depolarization and vasoconstriction in male mice mesenteric resistance arteries

Article

Author: Aalkjaer, Christian ; Simonsen, Ulf ; Chen, Hua

AbstractWe investigated whether sex differences exist in cyclooxygenase‐dependent effects on membrane potential and relaxation in mice mesenteric resistance arteries. Mesenteric small arteries of 9‐ to 12‐week‐old, male and female, wild‐type mice, db/+ mice and diabetic db/db mice were mounted in myographs for measurements of isobaric diameter and smooth muscle cell membrane potential. Acetylcholine caused smaller dilation of arteries from male db/+ mice compared to arteries from female db/+ mice. In the presence of the NO synthase inhibitor Nω‐nitro‐L‐arginine methyl ester (L‐NAME), acetylcholine‐induced dilation of arteries from males increased in the presence of indomethacin and the COX‐1‐specific inhibitor FR122047. The presence of indomethacin was also associated with a more negative membrane potential in arteries from males. In arteries from db/db mice, no sex differences were seen. In arteries from male but not female wild‐type mice, the thromboxane receptor blocker SQ29,548 increased relaxation to acetylcholine. In contrast to arteries from female mice, COX (most likely COX‐1)‐derived prostanoids and activation of thromboxane receptors counteract acetylcholine vasodilatation probably through increased smooth muscle depolarization in arteries from male mice. In mice with diabetes and pronounced endothelial dysfunction, inhibition of COX did not enhance acetylcholine vasodilatation.

01 Dec 2019·Life SciencesQ3 · MEDICINE

Altered cyclooxygenase-1 and enhanced thromboxane receptor activities underlie attenuated endothelial dilatory capacity of omental arteries in obesity

Q3 · MEDICINE

Article

Author: Al-Jaber, Mashael ; Abraham, David ; Mohamed-Ali, Vidya ; Raees, Asmaa ; Clapp, Lucie H ; Orie, Nelson N ; Bakhamis, Aysha ; Bashah, Moataz

AIMSObesity is a risk factor for endothelial dysfunction, the severity of which is likely to vary depending on extent and impact of adiposity on the vasculature. This study investigates the roles of cyclooxygenase isoforms and thromboxane receptor activities in the differential endothelial dilatory capacities of arteries derived from omental and subcutaneous adipose tissues in obesity.MAIN METHODSSmall arteries were isolated from omental and subcutaneous adipose tissues obtained from consented morbidly obese patients (n = 65, BMI 45 ± 6 kg m^-2 [Mean ± SD]) undergoing bariatric surgery. Relaxation to acetylcholine was studied by wire myography in the absence or presence of indomethacin (10 μM, cyclooxygenase inhibitor), FR122047 (1 μM, cyclooxygenase-1 inhibitor), Celecoxib (4 μM, cyclooxygenase-2 inhibitor), Nω-Nitro-L-arginine methyl ester (L-NAME, 100 μM, nitric oxide synthase inhibitor) or combination of apamin (0.5 μM) and charybdotoxin (0.1 μM) that together inhibit endothelium-derived hyperpolarizing factor (EDHF). Contractions to U46619 (thromboxane A₂ mimetic) were also studied.KEY FINDINGSAcetylcholine relaxation was significantly attenuated in omental compared with subcutaneous arteries from same patients (p < 0.01). Indomethacin (p < 0.01) and FR122047 (p < 0.001) but not Celecoxib significantly improved the omental arteriolar relaxation. Cyclooxygenase-1 mRNA and U46619 contractions were both increased in omental compared with subcutaneous arteries (p < 0.05). L-NAME comparably inhibited acetylcholine relaxation in both arteries, while apamin+charybdotoxin were less effective in omental compared with subcutaneous arteries.SIGNIFICANCEThe results show that the depot-specific reduction in endothelial dilatory capacity of omental compared with subcutaneous arteries in obesity is in large part due to altered cyclooxygenase-1 and enhanced thromboxane receptor activities, which cause EDHF deficiency.

100 Deals associated with ASP-6537

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Indication	Highest Phase	Country/Location	Organization	Date
Osteoarthritis	Preclinical	JP	Astellas Pharma, Inc.	01 Oct 2011
Rheumatoid Arthritis	Preclinical	JP	Astellas Pharma, Inc.	01 Oct 2011
Nervous System Diseases	Preclinical	-	Astellas Pharma, Inc.	-
Nervous System Diseases	Preclinical	-	Cardeus Pharmaceuticals, Inc.	-
Pain	Discovery	JP	Fujisawa Pharmaceutical Co., Ltd.	-
Thrombosis	Discovery	JP	Fujisawa Pharmaceutical Co., Ltd.	-

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