Disease relevance of Cicaprost

• Treatment with pertussis toxin reversed the inhibitory effects of cicaprost on CRE occupancy, cyclin E-cdk2 activity, and S phase entry, suggesting the involvement of Gi signaling in cicaprost action [1].
• In rats whose SMT2A tumors were surgically removed 10 days after tumor implantation, there was a strong decrease of lung metastases by cicaprost given from day 20 to day 36 [2].
• Antiatherosclerotic effects of oral cicaprost in experimental hypercholesterolemia in rabbits [3].
• Cicaprost also inhibited ET-1 induction of c-fos mRNA expression, an additional marker of hypertrophy in ARCM (n = 5, P < 0.005) [4].
• In Cop rats bearing spontaneously metastasizing R 3327 MAT Lu prostate carcinomas, cicaprost (1.0 mg/kg p.o. daily) inhibited the number of lung metastases by about 80%, whereas the lower doses (0.1 and 0.5 mg/kg) exhibited borderline efficacy [5].

High impact information on Cicaprost

• Depletion of PDE6delta using short interfering RNA abolished cicaprost-induced IP internalization in human aortic smooth muscle cells [6].
• Levels of the closely related Cdk2 inhibitor, p21(Cip1), are unaffected by cicaprost [7].
• Moreover, we show that cicaprost blocks the induction of Skp2 mRNA and that ectopic expression of a Skp2 cDNA overrides the effect of cicaprost on p27(Kip1) levels and S phase entry [7].
• First, we show that cicaprost prevents the late G(1) phase down-regulation of p27(Kip1) and that the inhibitory effect of cicaprost on cyclin E-Cdk2 activity and S phase entry is eliminated by deleting p27(Kip1) [7].
• Conversely, signaling by TP alpha S329A was insensitive to cicaprost stimulation whereas it was fully desensitized by NO/PKG signaling [8].

Chemical compound and disease context of Cicaprost

• Rodent model of systemic mammary tumor disease by surgical removal of the spontaneously metastasizing SMT2A mammary carcinoma: inhibitory effect of the stable prostacyclin analogue cicaprost on occult metastasis [2].
• The inhibitory effect of ILP and c-PGI(2) on AVP-stimulated L(p) is partially reversed by the protein kinase C inhibitor staurosporine and abolished by pertussis toxin; no effect was obtained with CCP [9].
• In contrast, neither glibenclamide (10 microM), a blocker of ATP-sensitive K+ channels, nor fluoxetine hydrochloride (100 microM), a blocker of G-protein-gated inward rectifier K+ channels, nor pertussis toxin (PTX; 1 microg/ml), which irreversibly inhibits Gi/Go, reduced relaxation to cicaprost [10].
• Effects of cicaprost and fosinopril on the progression of rat diabetic nephropathy [11].

Biological context of Cicaprost

• Consistent with previous studies, cicaprost abrogated U46619-mediated platelet aggregation and mobilization of intracellular calcium ([Ca(2+)](i)) [12].
• Whole cell phosphorylation assays demonstrated that the mIP undergoes cicaprost-induced PKA phosphorylation. mIP(S357A), a site-directed mutant of mIP, efficiently coupled to G alpha(s) but failed to couple to G alpha(i) or to efficiently couple to G alpha(q):PLC [13].
• OBJECTIVE: We investigated the role of the inward rectifier potassium (KIR) channel and the cyclic AMP-dependent pathway in mediating vasorelaxation induced by the prostacyclin analogue cicaprost [10].
• Serum-induced proliferation, as assessed by [(3)H]thymidine incorporation (30 h) or cell number (48 h), was significantly inhibited with a 10-fold difference in potency, ranking in effectiveness UT-15 > iloprost > cicaprost > beraprost [14].
• Cicaprost was used as the test agonist because of its high stability, selectivity and potency (IC50 = 3.8 nM) [15].

Anatomical context of Cicaprost

• 2. On piglet saphenous vein, PGE(2) was 6.1, 24, 96, 138, 168 and 285 times respectively more potent than AFP-07, cicaprost, PGI(2), iloprost, carbacyclin and TEI-9063 in causing relaxation [16].
• KEY RESULTS: RO1138452 antagonized relaxation of human pulmonary artery, guinea-pig aorta and rabbit mesenteric artery induced by the selective IP agonist cicaprost [17].
• In addition, platelet and leukocyte hyperreactivity, as seen in hypercholesterolemic rabbits, were largely reduced by cicaprost treatment [3].
• AH 23848 did not block cicaprost-induced relaxation of piglet carotid artery [16].
• On human and pig membranes the order of potency was cicaprost = iloprost greater than 6a-carba PGI2 greater than EP 157 [18].

Associations of Cicaprost with other chemical compounds

• Moreover, the prostacyclin mimetic, cicaprost, and the cAMP analogue, dibutyryl cAMP, inhibited GM-CSF release from these cells [19].
• In functional studies, PGI2 and its analogs, iloprost and cicaprost, were able to stimulate LHRH release from the GT1-1 cells with elevated potencies (EC50 = 0.6-4.3 nM); PGE1 was only slightly less active (EC50 = 28.5 nM), whereas PGE2, considered the major PG involved in LHRH secretion, was poorly effective (EC50 = 921 nM) [20].
• METHODS: Small vessel myography was used to assess responses to cicaprost in segments of rat tail artery contracted with phenylephrine [10].
• In the same samples, the LPS-stimulated production of TNF was markedly attenuated by rolipram or cicaprost [21].
• The selective adenosine A1-receptor antagonist, DPCPX, used at a sufficiently high concentration (5 microM) to block adenosine A2-receptors, did not affect cicaprost inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)[15]

Gene context of Cicaprost

• Semiquantitative rt-PCR measurements showed a marked decrease of TNF-alpha- and IL-1 beta-induced mRNA levels of both adhesion molecules after preincubation with cicaprost [22].
• The stability of TNF-alpha-induced ICAM-1 and VCAM-1 expression at mRNA and protein level was not altered by cicaprost [22].
• Stimulation of endogenous hIP by its specific agonist, cicaprost, resulted in STAT3 Tyr705 and Ser727 phosphorylations in a time- and concentration-dependent manner [23].
• Cicaprost-induced STAT3 Tyr705 and Ser727 phosphorylations were resistant to pertussis toxin (PTX) treatment, suggesting that these responses were mediated through PTX-insensitive G proteins [23].
• Similar observations were obtained with STAT1 upon stimulation by cicaprost [23].

Analytical, diagnostic and therapeutic context of Cicaprost

• 2. We have investigated the pharmacological effects of cicaprost, a synthetic PGI2 analogue which is metabolically stable and bioavailable after oral administration, in eight healthy male volunteers [24].
• Cicaprost also induced a significant elevation in RPF and a significant decrease in filtration fraction [25].
• Plasma and urine levels of cicaprost were measured with a sensitive radioimmunoassay on the last treatment day [26].
• Longer studies with dose titration are probably needed to demonstrate the beneficial effects, if any, of cicaprost in patients with Raynaud's secondary to SSc, and these are being planned [27].
• Thus, cicaprost is an orally available PGI2-mimetic, for which effects on platelet aggregation and vascular perfusion have been demonstrated in healthy volunteers after doses of 5 to 15 micrograms [28].

References