Novel dual inhibitors of vascular endothelial growth factor and VEGFR2 receptor

Nguyen, Jennifer P.; Frost, Chelsea; Lane, Meghan L.; Skelton, William Paul; Skelton, Michelle; Vesely, David L.

doi:10.1111/j.1365-2362.2012.02695.x

Cited by 21 publications

(27 citation statements)

References 23 publications

(67 reference statements)

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“…These four cardiac hormones decrease the VEGFR2 receptor by up to 89% in human small-cell lung cancer cells and up to 92% in human prostate cancer cells (Nguyen et al 2012). These results were confirmed by Western blot that revealed a cardiac hormone-mediated decrease in VEGFR2 receptor (Nguyen et al 2012).…”

Section: Vascular Endothelial Growth Factorsupporting

confidence: 72%

“…The four cardiac hormones maximally decrease the VEGFR2 receptor in human pancreatic adenocarcinoma cells up to 83% (Nguyen et al 2012). These four cardiac hormones decrease the VEGFR2 receptor by up to 89% in human small-cell lung cancer cells and up to 92% in human prostate cancer cells (Nguyen et al 2012).…”

Section: Vascular Endothelial Growth Factormentioning

confidence: 99%

“…The cardiac hormones reduce VEGF concentrations up to 58% (Nguyen et al 2012). Although there are a number of compounds that inhibit VEGF or its VEGFR2 receptor, the cardiac hormones are the first agents that are dual inhibitors of VEGF and its VEGFR2 receptor (Nguyen et al 2012). …”

Section: Vascular Endothelial Growth Factormentioning

confidence: 99%

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Cardiac hormones for the treatment of cancer

Vesely¹

2013

Endocrine-Related Cancer

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Four cardiac hormones, namely atrial natriuretic peptide, vessel dilator, kaliuretic peptide, and long-acting natriuretic peptide, reduce up to 97% of all cancer cells in vitro. These four cardiac hormones eliminate up to 86% of human small-cell lung carcinomas, two-thirds of human breast cancers, and up to 80% of human pancreatic adenocarcinomas growing in athymic mice. Their anticancer mechanisms of action, after binding to specific receptors on cancer cells, include targeting the rat sarcoma-bound GTP (RAS) (95% inhibition)-mitogen-activated protein kinase kinase 1/2 (MEK 1/2) (98% inhibition)-extracellular signal-related kinase 1/2 (ERK 1/2) (96% inhibition) cascade in cancer cells. They also inhibit MAPK9, i.e. c-Jun N-terminal kinase 2. They are dual inhibitors of vascular endothelial growth factor (VEGF) and its VEGFR2 receptor (up to 89%). One of the downstream targets of VEGF is b-catenin, which they reduce up to 88%. The WNT pathway is inhibited up to 68% and secreted frizzled-related protein 3 decreased up to 84% by the four cardiac hormones. AKT, a serine/threonine protein kinase, is reduced up to 64% by the cardiac hormones. STAT3, a final 'switch' that activates gene expression that leads to malignancy, is decreased by up to 88% by the cardiac hormones. STAT3 is specifically decreased as they do not affect STAT1. There is a cross-talk between the RAS-MEK 1/2-ERK 1/2 kinase cascade, VEGF, b-catenin, WNT, JNK, and STAT pathways and each of these pathways is inhibited by the cardiac hormones.

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Section: Vascular Endothelial Growth Factorsupporting

confidence: 72%

Section: Vascular Endothelial Growth Factormentioning

confidence: 99%

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Cardiac hormones for the treatment of cancer

Vesely¹

2013

Endocrine-Related Cancer

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“…After binding to their respective receptors on the tumor cells, all the four natriuretic peptides inhibit some metabolic targets including the GTPase RAS [21], the MEK1/2 kinase [22] and the extracellular signal-regulated kinase (ERK) 1/2 [23]. In addition to its ability of inhibiting the Ras-MEK1⁄2-ERK1⁄2 kinase cascade, functioning as a multikinase inhibitor, it has been recently reported that ANP (as well as the other three natriuretic hormones) is able to decrease, in tumor cells, the levels of vascular endothelial growth factor (VEGF) and its main receptor VEGFR2 [24], and of the Signal Transducer and Activator of Transcription 3 (STAT 3)[25], that are three molecular targets useful for cancer therapy [26-28]. Moreover, owing the observed localization of ANP in the nuclear compartment of human pancreatic adenocarcinoma cells, a direct interaction of the peptide with growth-promoting hormones in the nucleus has been hypothesized [29].…”

Section: Mechanism(s) Of Action Of Anp: Specific Receptors and Metabomentioning

confidence: 99%

Atrial Natriuretic Peptide: A Magic Bullet for Cancer Therapy Targeting Wnt Signaling and Cellular pH Regulators

Serafino¹,

Pierimarchi

2014

CMC

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Atrial natriuretic peptide (ANP) is a cardiac hormone playing a crucial role in cardiovascular homeostasis mainly through blood volume and pressure regulation. In the last years, the new property ascribed to ANP of inhibiting tumor growth both in vitro and in vivo has made this peptide an attractive candidate for anticancer therapy. The molecular mechanism underlying the anti-proliferative effect of ANP has been mainly related to its interaction with the specific receptors NPRs, through which this natriuretic hormone inhibits some metabolic targets critical for cancer development, including the Ras-MEK1⁄2-ERK1⁄2 kinase cascade, functioning as a multikinase inhibitor. In this review we summarize the current knowledge on this topic, focusing on our recent data demonstrating that the antitumor activity of this natriuretic hormone is also mediated by a concomitant effect on the Wnt/β-catenin pathway and on the pH regulation ability of cancer cells, through a Frizzled-related mechanism. This peculiarity of simultaneously targeting two processes crucial for neoplastic transformation and solid tumor survival reinforces the utility of ANP for the development of both preventive and therapeutic strategies.

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“…88 These 4 cardiac hormones also decrease VEGF’s concentrations up to 58%. 88 These cardiac hormones are, thus, the first dual inhibitors of VEGF and its R2 receptor, as there are no compounds that inhibit both, although there are compounds that inhibit VEGF and other compounds that inhibit the VEGFR2 receptor. 88 …”

Section: Ras-mek 1/2 - Erk 1/2 Kinase Cascadementioning

confidence: 99%

Natriuretic Peptides’ Metabolic Targets for Treatment of Cancer

Vesely

2013

Journal of Investigative Medicine

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Four cardiac hormones are synthesized by the atrial natriuretic peptide prohormone gene. These hormones, namely, long-acting natriuretic peptide, vessel dilator, kaliuretic peptide, and atrial natriuretic peptide, help regulate blood pressure and blood volume by causing vasodilation, diuresis, and sodium excretion. These cardiac hormones reduce up to 97% of all cancer cells in vitro. These cardiac hormones eliminate up to 86% of human small-cell lung carcinomas, two thirds of human breast cancers, and up to 80% of human pancreatic adenocarcinomas growing in athymic mice. Their anticancer mechanisms of action, after binding to specific receptors on cancer cells, include targeting the Rat sarcoma-bound guanosine diphosphate conversion to RAS guanosine triphosphate (95% inhibition)-mitogen-activated protein kinase kinase 1/2 (98% inhibition)-extracellular signal-related kinase 1/2 (96% inhibition) cascade in cancer cells. They also reduce c-Jun-N-terminal kinase 2 up to 89%. These multiple kinase inhibitors are also inhibitors of vascular endothelial growth factor (VEGF) and its VEGFR2 receptor (up to 89% inhibition). They reduce β-catenin up to 88%. They inhibit the WNT pathway up to 68%, and secreted Frizzled-related protein 3 is decreased up to 84%. AKT, a serine/threonine-protein kinase, is reduced up to 64% by the cardiac hormones. Signal transducer and activator of transcription 3, a final "switch" that activates gene expression that leads to malignancy, is decreased by up to 88% by the cardiac hormones. Of importance, the cross talk between the multiple kinases, VEGF, B-catenin, WNT, and STAT pathways is inhibited by the 4 cardiac hormones.

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Novel dual inhibitors of vascular endothelial growth factor and VEGFR2 receptor

Abstract: Four cardiac hormones are the first dual inhibitors of VEGF and the VEGFR2/KDR/Flk-1 receptor.

Cited by 21 publications

References 23 publications

Cardiac hormones for the treatment of cancer

Cardiac hormones for the treatment of cancer

Atrial Natriuretic Peptide: A Magic Bullet for Cancer Therapy Targeting Wnt Signaling and Cellular pH Regulators

Natriuretic Peptides’ Metabolic Targets for Treatment of Cancer

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