Pharmacological profile of a novel carbacyclin derivative with high metabolic stability and oral activity in the rat

Stürzebecher, S; Haberey, Martin; Müller, B.; Schillinger, E.; Schröder, G.; Skuballa, Werner; Stock, Günter; Vorbrüggen, Helmut; Witt, Werner

doi:10.1016/0090-6980(86)90228-5

Cited by 73 publications

(23 citation statements)

References 12 publications

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“…Cicaprost (61), which is known to elevate cAMP in many tissues, also enhanced G-CSF release from HASM cells, implicating adenylyl cyclase-coupled IP receptors in this response. Although selective antagonists that would confirm this assertion are unavailable, this interpretation is supported by several pieces of evidence.…”

Section: Discussionmentioning

confidence: 90%

Prostanoid receptor expression by human airway smooth muscle cells and regulation of the secretion of granulocyte colony-stimulating factor

Clarke¹,

Belvisi²,

Smith³

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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receptor expression by human airway smooth muscle cells and regulation of the secretion of granulocyte colony-stimulating factor. Am J Physiol Lung Cell Mol Physiol 288: L238 -L250, 2005; doi:10.1152/ ajplung.00313.2004.-The prostanoid receptors on human airway smooth muscle cells (HASMC) that augment the release by IL-1␤ of granulocyte colony-stimulating factor (G-CSF) have been characterized and the signaling pathway elucidated. PCR of HASM cDNA identified products corresponding to EP 2, EP3, and EP4 receptor subtypes. These findings were corroborated at the protein level by immunocytochemistry. IL-1␤ promoted the elaboration of G-CSF, which was augmented by PGE2. Cicaprost (IP receptor agonist) was approximately equiactive with PGE2, whereas PGD2, PGF2␣, and U-46619 (TP receptor agonist) were over 10-fold less potent. Neither SQ 29,548 nor BW A868C (TP and DP1 receptor antagonists, respectively) attenuated the enhancement of G-CSF release evoking any of the prostanoids studied. With respect to PGE2, the EP receptor agonists 16,16-dimethyl PGE2 (nonselective), misoprostol (EP2/EP3 selective), 17-phenyl--trinor PGE2 (EP1 selective), ONO-AE1-259, and butaprost (both EP2 selective) were full agonists at enhancing G-CSF release. AH 6809 (10 M) and L-161,982 (2 M), which can be used in HASMC as selective EP2 and EP4 receptor antagonists, respectively, failed to displace to the right the PGE2 concentrationresponse curve that described the augmented G-CSF release. In contrast, AH 6809 and L-161,982 in combination competitively antagonized PGE2-induced G-CSF release. Augmentation of G-CSF release by PGE 2 was mimicked by 8-BrcAMP and abolished in cells infected with an adenovirus vector encoding an inhibitor protein of cAMP-dependent protein kinase (PKA). These data demonstrate that PGE2 facilitates G-CSF secretion from HASMC through a PKAdependent mechanism by acting through EP2 and EP4 prostanoid receptors and that effective antagonism is realized only when both subtypes are blocked concurrently.cAMP-dependent protein kinase; human airway smooth muscle; granulocyte colony-stimulating factor; prostanoid receptors; airway inflammation

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Section: Discussionmentioning

confidence: 90%

Prostanoid receptor expression by human airway smooth muscle cells and regulation of the secretion of granulocyte colony-stimulating factor

Clarke¹,

Belvisi²,

Smith³

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…15 The ability of three other prostacyclin analogues to inhibit monocytic cell tissue factor induction was investigated. As shown in Figure 2, an orally active analogue, cicaprost, 24 was equipotent with iloprost in inhibiting endotoxin-induced tissue factor expression. Carbacyclin and ciprostene were approximately two orders of magnitude less potent.…”

Section: Discussionmentioning

confidence: 93%

Prostacyclin analogues inhibit tissue factor expression in the human monocytic cell line THP-1 via a cyclic AMP-dependent mechanism.

Crutchley

Solomon

Conanan

1992

Arterioscler Thromb

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Increased expression of tissue factor procoagulant by peripheral blood monocytes has been implicated in a number of thrombotic disorders. The present studies were undertaken to determine whether stable analogues of prostacyclin, a potent endothelium-derived platelet inhibitor and vasodilator, could inhibit tissue factor expression by human monocytic cells. Exposure of monocytic tumor THP-1 cells to 100 ng/ml endotoxin, 2 units/ml interleukin-1 beta, or 5 ng/ml tumor necrosis factor-alpha for 4 hours led to increased tissue factor procoagulant activity. Preincubation for 30 minutes with iloprost, ciprostene, and carbacyclin led to a dose-dependent inhibition of tissue factor expression induced by all three challenging agents. Iloprost was the most potent: 50% inhibition occurred at 5 nM, a concentration close to the reported dissociation constant for iloprost binding to the platelet prostacyclin receptor. An orally active analogue, cicaprost, was equally effective against endotoxin-induced tissue factor expression. Carbacyclin and ciprostene were 100 times less potent. Iloprost prevented the endotoxin-induced expression of tissue factor antigen on the surface of THP-1 cells, as determined by flow cytometry. Iloprost (500 pM-50 nM) increased intracellular levels of cyclic AMP. This effect was potentiated by isobutylmethylxanthine, an inhibitor of phosphodiesterase. The inhibitory effects of iloprost on tissue factor expression were also potentiated by isobutylmethylxanthine and mimicked by forskolin and dibutyryl cyclic AMP but not dibutyryl cyclic GMP. These results suggest that prostacyclin may play a role in downregulating tissue factor expression in monocytes, at least in part via elevation of intracellular levels of cyclic AMP.

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“…However, cicaprost (Table 3, entry 5), which contains a 3-oxo group, has a longer half-life of 1-2 h and its clearance was only~20% of that of iloprost (Hildebrand et al, 1989); additionally, 80% of the dose was excreted unchanged, which is consistent with improved metabolic stability. Further β-oxidation-resistant ethers were prepared, including the prostacyclin analogue 3-oxa-iloprost (Stürzebecher et al, 1986), and stable analogues of PGE 2 (Elworthy et al, 2004) (Table 3, entry 6) and lipoxin (Table 3, entry 7) (Guilford et al, 2004). In general the biological activities of the parent compound were conserved in this approach and β-oxidation was prevented, but not always with a corresponding improvement in pharmacokinetic profile.…”

Section: β-Oxidationmentioning

confidence: 99%

Anti-tumor activities of lipids and lipid analogues and their development as potential anticancer drugs

Murray

Hraiki

Bebawy

et al. 2015

Pharmacology & Therapeutics

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Lipids have the potential for development as anticancer agents. Endogenous membrane lipids, such as ceramides and certain saturated fatty acids, have been found to modulate the viability of tumor cells. In addition, many tumors over-express cyclooxygenase, lipoxygenase or cytochrome P450 enzymes that mediate the biotransformation of ω-6 polyunsaturated fatty acids (PUFAs) to potent eicosanoid regulators of tumor cell proliferation and cell death. In contrast, several analogous products from the biotransformation of ω-3 PUFAs impair particular tumorigenic pathways. For example, the ω-3 17,18-epoxide of eicosapentaenoic acid activates anti-proliferative and proapoptotic signaling cascades in tumor cells and the lipoxygenase-derived resolvins are effective inhibitors of inflammatory pathways that may drive tumor expansion. However, the development of potential anti-cancer drugs based on these molecules is complex, with in vivo stability a major issue. Nevertheless, recent successes with the antitumor alkyl phospholipids, which are synthetic analogues of naturally-occurring membrane phospholipid esters, have provided the impetus for development of further molecules. The alkyl phospholipids have been tested against a range of cancers and show considerable activity against skin cancers and certain leukemias. Very recently, it has been shown that combination strategies, in which alkyl phospholipids are used in conjunction with established anticancer agents, are promising new therapeutic approaches. In future, the evaluation of new lipid-based molecules in single-agent and combination treatments may also be assessed. This could provide a range of important treatment options in the management of advanced and metastatic cancer.

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Pharmacological profile of a novel carbacyclin derivative with high metabolic stability and oral activity in the rat

Cited by 73 publications

References 12 publications

Prostanoid receptor expression by human airway smooth muscle cells and regulation of the secretion of granulocyte colony-stimulating factor

Prostanoid receptor expression by human airway smooth muscle cells and regulation of the secretion of granulocyte colony-stimulating factor

Prostacyclin analogues inhibit tissue factor expression in the human monocytic cell line THP-1 via a cyclic AMP-dependent mechanism.

Anti-tumor activities of lipids and lipid analogues and their development as potential anticancer drugs

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