Everolimus

Houghton, Peter J.

doi:10.1158/1078-0432.ccr-09-1314

Cited by 184 publications

(129 citation statements)

References 24 publications

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“…Such efforts culminated in the development of rapamycin analogs temsirolimus (cell cycle inhibitor-779 (CCI-779)), everolimus (RAD-001), and ridaforolimus (AP23573; also known as MK-8669) with slightly improved bioavailability (33). The first two are approved for human use in the treatment of advanced renal cell carcinoma and are currently in clinical trials for various solid tumors and hematopoietic malignancies (34,35). AP23573 is currently in clinical trials for advanced soft tissue and bone sarcomas, endometrial cancer, and hematopoietic malignancies (36).…”

Section: Mammalian Target Of Rapamycin (Mtor)mentioning

confidence: 99%

Structure-Activity Analysis of Niclosamide Reveals Potential Role for Cytoplasmic pH in Control of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling

Fonseca

Diering

Bidinosti

et al. 2012

Journal of Biological Chemistry

143

122

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Background: mTORC1 is dysregulated in human disease, and there is an interest in the development of mTORC1 inhibitors. Niclosamide inhibits mTORC1 signaling, but its mode of action remains unclear. Results: Niclosamide extrudes protons from lysosomes, thus lowering cytoplasmic pH and inhibiting mTORC1 signaling. Conclusion: Cytoplasmic acidification inhibits mTORC1 signaling. Significance: Our findings may aid the design of niclosamide-based anticancer therapeutic agents.

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Section: Mammalian Target Of Rapamycin (Mtor)mentioning

confidence: 99%

Structure-Activity Analysis of Niclosamide Reveals Potential Role for Cytoplasmic pH in Control of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling

Fonseca

Diering

Bidinosti

et al. 2012

Journal of Biological Chemistry

143

122

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“…Similar to rapamycin, everolimus and cyclophilin FKBP-12 complex binds to the serine/threonine kinase mTOR and inhibits downstream signalling pathways for cell growth and proliferation (10)(11)(12). Although initially developed for the acute and chronic rejection of cardiac, liver, lung, and renal transplant recipients, everolimus is currently being used for the treatment of many cancer types, including renal cell carcinoma, pancreatic neuroendocrine tumors, and breast cancer (13,14).…”

Section: Introductionmentioning

confidence: 99%

Effects of everolimus on a rat model of cerulein-induced experimental acute pancreatitis

Özkardeş¹,

Bozkurt²,

Dumlu³

et al. 2015

UCD

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Objective: To analyze the biochemical and histopathological effects of everolimus in an experimental rat model of cerulein-induced acute pancreatitis. The aim of the present study was to determine the effects of everolimus on blood biochemical parameters and tissue histopathology in an experimental rat model of cerulein-induced acute pancreatitis. Material and Methods:In 30 Wistar albino rats (male; 240-260 g), acute pancreatitis was induced by an intraperitoneal injection of cerulein (50 μg/kg) administered twice in 2 h. They were equally divided into the following three groups: 0.9% isotonic solution (Group 1; control), everolimus once (Group 2), and everolimus twice (Group 3) by oral gavage after cerulein injection. Thirty hours after the induction of pancreatitis, blood samples were collected by direct intracardiac puncture, rats were sacrificed, and pancreatic tissue samples were obtained.Results: Biochemical analyses of the blood samples showed statistically significant difference in red blood cell count as well as hemoglobin, hematocrit, urea, and alanine transaminase levels among the study groups (p<0.05 in all). Everolimus proved to significantly increase red blood cell count in a dose-independent manner. Hemoglobin and hematocrit levels significantly increased only after treatment with one dose of everolimus. Urea level was significantly different between the Groups 2 and 3; however, no change was observed in both groups when compared with the control. Alanine transaminase level significantly decreased only after treatment with two doses of everolimus. Histopathological analyses revealed that everolimus significantly decreased inflammation and perivascular infiltrate in a dose-dependent manner (35% in Group 2, 75% in Group 3; p=0.048). Conclusion:Treatment with two doses of everolimus improved some biochemical and histopathological parameters of experimental rat models of cerulein-induced acute pancreatitis and implied the specific inhibition of inflammatory response pathways. Keywords: Pancreatitis, cerulein, everolimus, inflammation INTRODUCTIONAcute pancreatitis is a localized inflammatory condition with a high mortality rate (2.1%-9.2%) worldwide. Because of its potential to trigger systemic inflammatory response, it can cause multiple organ failure (1, 2). The common causes of acute pancreatitis are alcohol abuse or gallstone disease (60%-75% of the cases) followed by hypertriglyceridemia, hyperparathyroidism, pancreatic malignancy, endoscopic retrograde cholangiopancreatography, trauma, infectious agents (increasingly associated with HIV infection), drugs (such as tetracycline, azathioprine, ethinyl estradiol, mercaptopurine, and sulfamethoxazole), autoimmunity, abdominal trauma, ischemia, diabetes mellitus, porphyria, and heredity (3-5).Although the disease is common, the treatment of acute pancreatitis is still very limited. There are only a number of pharmacological approaches, which are mostly supportive involving adequate fluid resuscitation and oxygen supplementation, to maintain normal art...

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“…Everolimus, a derivative of rapamycin, acts as a signal transduction inhibitor. Its molecular target is the mammalian target of rapamycin (mTOR), a component in the PI3K/Akt/mTOR pathway known to be very frequently activated in human cancers (Houghton 2010) and a frequent characteristic of worsening prognosis, resistance to treatment, extension of disease, and progression. Everolimus has been shown to suppress expression of hypoxia-inducible factor-1 (HIF1) and VEGF in cultured tumor cells and also to reduce blood vessel density in several different experimental tumor models (Shinohara et al 2005, Mabuchi et al 2007a.…”

Section: Introductionmentioning

confidence: 99%

Combination of sorafenib and everolimus impacts therapeutically on adrenocortical tumor models

Mariniello¹,

Rosato²,

Zuccolotto³

et al. 2012

Endocrine-Related Cancer

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Treatment options are insufficient in patients with adrenocortical carcinoma (ACC). Based on the efficacy of sorafenib, a tyrosine kinase inhibitor, and everolimus, an inhibitor of the mammalian target of rapamycin in tumors of different histotype, we aimed at testing these drugs in adrenocortical cancer models. The expression of vascular endothelial growth factor and its receptors (VEGFR1-2) was studied in 18 ACCs, 33 aldosterone-producing adenomas, 12 cortisol-producing adenomas, and six normal adrenal cortex by real-time PCR and immunohistochemistry and by immunoblotting in SW13 and H295R cancer cell lines. The effects of sorafenib and everolimus, alone or in combination, were tested on primary adrenocortical cultures and SW13 and H295R cells by evaluating cell viability and apoptosis in vitro and tumor growth inhibition of tumor cell line xenografts in immunodeficient mice in vivo. VEGF and VEGFR1-2 were detected in all samples and appeared over-expressed in two-thirds of ACC specimens. Dose-dependent inhibition of cell viability was observed particularly in SW13 cells after 24 h treatment with either drug; drug combination produced markedly synergistic growth inhibition. Increasing apoptosis was observed in tumor cells treated with the drugs, particularly with sorafenib. Finally, a significant mass reduction and increased survival were observed in SW13 xenograft model undergoing treatment with the drugs in combination. Our data suggest that an autocrine VEGF loop may exist within ACC. Furthermore, a combination of molecularly targeted agents may have both antiangiogenic and direct antitumor effects and thus could represent a new therapeutic tool for the treatment of ACC.

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Everolimus

Abstract: Everolimus, an orally administered rapamycin analog, has recently been approved by the U

Cited by 184 publications

References 24 publications

Structure-Activity Analysis of Niclosamide Reveals Potential Role for Cytoplasmic pH in Control of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling

Structure-Activity Analysis of Niclosamide Reveals Potential Role for Cytoplasmic pH in Control of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling

Effects of everolimus on a rat model of cerulein-induced experimental acute pancreatitis

Combination of sorafenib and everolimus impacts therapeutically on adrenocortical tumor models

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