Rapamycin treatment is associated with an increased apoptosis rate in experimental vein grafts☆

Schachner, Thomas; Oberhuber, Alexander; Zou, Yping; Tzankov, Alexandar; Ott, Harald C.; Laufer, Günther; Bonatti, Johannes

doi:10.1016/j.ejcts.2004.11.008

Cited by 31 publications

(20 citation statements)

References 23 publications

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“…This observation is also in agreement with previous studies [56]. Previously, decreased levels of anti-apoptotic proteins through inhibition of nuclear translocation of NF-KB protein [57] or by activation of Fas and Fas ligand pathway have been suggested as the most likely mechanisms by which sirolimus increases apoptosis in endothelial cells and vascular smooth muscle cells [58].…”

Section: Discussionsupporting

confidence: 91%

Use of a novel anti-proliferative compound coated on a biopolymer to mitigate platelet-derived growth factor-induced proliferation in human aortic smooth muscle cells: comparison with sirolimus

et al. 2008

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Drug eluting stents (DES) have become a common mode of treatment for stenosis in coronary arteries. However, currently, the use of sirolimus/paclitaxel-coated DES has come under scrutiny, because of their pro-thrombotic effects leading to potential adverse outcomes in the long run. We have previously documented that D: -threo-1-phenyl-2-decanoylamino-3-morholino propanol (D-PDMP); an inhibitor of glucosylceramide synthase and lactosylceramide (LacCer) synthase markedly inhibited platelet-derived growth factor (PDGF)-induced cell proliferation. We have fabricated DES wherein, D-PDMP or sirolimus was coated on to a double layer of poly (lactic-co-glycolic acid) on a bare metal stent. The in vitro release of D-PDMP from biopolymer and its consequent effect on PDGF induced proliferation and apoptosis was assessed in human aortic smooth muscle cells (ASMC). D-PDMP was released from biopolymers in a dose-dependent fashion and was accompanied with a decrease in PDGF-induced cell proliferation, but not apoptosis. In contrast, sirolimus markedly increased apoptosis in these cells in addition to inhibiting proliferation. Our mechanistic studies revealed that D-PDMP, but not sirolimus decreased the cellular level of glucosyl and lactosylceramide that accompanied inhibition of PDGF-induced cell proliferation. Our short-term (14 days) in vivo studies in rabbits also attested to the safety and biocompatibility of the D-PDMP coated stents. Our data reveal the superiority of D-PDMP coated biopolymers over sirolimus coated biopolymers in mitigating ASMC proliferation. Such D-PDMP coated stents may be useful for localized delivery of drug to mitigate neo-vascular hyperplasia and other proliferative disorders.

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Section: Discussionsupporting

confidence: 91%

Use of a novel anti-proliferative compound coated on a biopolymer to mitigate platelet-derived growth factor-induced proliferation in human aortic smooth muscle cells: comparison with sirolimus

et al. 2008

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“…This indicates that CCI-779 induces apoptosis, which is consistent with the higher levels of cleaved caspase-9 found in CCI-779-treated tumors. Others have also reported that rapamycin or CCI-779 may exert an antitumor effect by inducing apoptosis (El-Hashemite et al, 2004;Frost et al, 2004;Avellino et al, 2005;Kenerson et al, 2005;Schachner et al, 2005). The fact that the IFN-g-treated tumors did not exhibit more apoptosis than untreated tumors is puzzling, given our observations of elevated cleaved caspases in these tumors.…”

Section: Discussionmentioning

confidence: 51%

Combination of a rapamycin analog (CCI‐779) and interferon‐γ is more effective than single agents in treating a mouse model of tuberous sclerosis complex

Lee

Sudentas

Dabora

2006

Genes Chromosomes & Cancer

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Tuberous sclerosis complex (TSC) is a familial tumor syndrome characterized by the development of hamartomas in the brain, heart, kidney, and skin. Disease-causing mutations in the TSC1 or TSC2 gene result in constitutive activation of the highly conserved mTOR signal transduction pathway, which regulates cell growth, proliferation, and metabolism. The mTOR inhibitor, rapamycin (sirolimus), reduces disease severity in rodent models of TSC, and is currently in phase II clinical trials. The cytokine interferon-gamma (IFN-gamma) is another potential therapeutic agent for TSC. A high-expressing IFN-gamma allele is associated with a lower frequency of kidney tumors in TSC patients, and treatment with exogenous IFN-gamma reduces the severity of TSC-related disease in mouse models. Here, we examine the effects of treating tumor-bearing nude mice with a combination of a rapamycin analog (CCI-779) and IFN-gamma. We observed that combination therapy was more effective than single agent therapy in reducing tumor growth and improving survival in this mouse model of TSC. Immunoblot and immunohistochemical analyses showed that tumors treated with CCI-779 plus IFN-gamma had decreased cell proliferation and increased cell death in comparison with untreated tumors or tumors treated with either agent alone. We also observed that CCI-779 resistance could develop with prolonged treatment. Taken together, our results show that targeting multiple cellular pathways is an effective strategy for treating TSC-related tumors, and underscore the importance of investigating combination therapy in future clinical trials for patients with TSC.

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“…Daemen 28 showed that inhibition of apoptosis prevents inflammation and tissue injury and that a monocyte chemoattractant, EMAP-II, is the molecule linking apoptosis and inflammation. Sirolimus, although possibly increasing apoptosis rate in vein grafts, 29 at the same time lowers the expression of EMAP-II in SM cells, reducing their adhesiveness for monocytes and preventing local inflammation. 26 …”

Section: P R E V E N T I O N O F R E S T E N O S I Smentioning

confidence: 97%

Molecular activity of sirolimus and its possible application in tuberous sclerosis treatment

Jóźwiak

Ołdak

2005

Medicinal Research Reviews

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Sirolimus is one of the intensively investigated drugs with pluripotent activities. It binds to its intracellular receptor FKBP12 (FK506-binding protein 12), a member of the family of FK506-binding proteins, and inhibits the activity of mTOR, a serine/threonine kinase involved in numerous cell processes linked to cell growth control. The drug is currently registered for the prophylaxis of organ rejection and for use in coronary stents. However, unique characteristics of sirolimus make it a good candidate for anti-cancer therapy. Indeed, phase II and III clinical studies in humans with several types of neoplasms are already under way. The review describes molecular activity of sirolimus and its analogs, characteristic for specific applications, in view of very recent advances involving tuberous sclerosis complex (TSC)-mediated signaling pathways. Current studies with sirolimus performed in tuberous sclerosis animal models are presented. Possible application of sirolimus for treating tuberous sclerosis, disease caused by mutations of TSC proteins, is discussed.

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Rapamycin treatment is associated with an increased apoptosis rate in experimental vein grafts☆

Cited by 31 publications

References 23 publications

Use of a novel anti-proliferative compound coated on a biopolymer to mitigate platelet-derived growth factor-induced proliferation in human aortic smooth muscle cells: comparison with sirolimus

Use of a novel anti-proliferative compound coated on a biopolymer to mitigate platelet-derived growth factor-induced proliferation in human aortic smooth muscle cells: comparison with sirolimus

Combination of a rapamycin analog (CCI‐779) and interferon‐γ is more effective than single agents in treating a mouse model of tuberous sclerosis complex

Molecular activity of sirolimus and its possible application in tuberous sclerosis treatment

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