Natriuretic Peptides’ Metabolic Targets for Treatment of Cancer

Abstract

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.

Pleiotropic Roles of Atrial Natriuretic Peptide in Anti-Inflammation and Anti-Cancer Activity

“…EGF and insulin were shown to stimulate ERK 1/2 kinases through mediating conversion of RAS-GDP to active RAS-GTP [ 90 ]. What is more, ANPs could block the activation of RAS and ERK 1/2 by mitogens such as insulin and epidermal growth factor (EGF) [ 91 ].…”

Serum atrial natriuretic peptide: a suspected biomarker of breast cancer

“…The molecular mechanism underlying the anticancer and anti-proliferative effect of ANP has been mainly related to its interaction with the specific natriuretic peptide receptors (NPRs) and inhibition of some metabolic targets critical for cancer development, including the Ras-MEK1⁄2, ERK1⁄2 kinase cascade [12, 13], Wnt pathway [14, 15], VEGF, and B-catenin [16]. DNA synthesis is also inhibited within the nucleus; this inhibition is mediated by the intracellular mediator cyclic GMP [17].…”

Role of atrial natriuretic peptide receptor in inhibition of laterally spreading tumors via Wnt/β-catenin signaling

“…ANPs can slow progression of prostate, breast, pancreatic and colorectal adenomas. At present, it is believed that the potential anticancer mechanisms of ANPs include inhibition of DNA synthesis through intracellular messenger DNA [ 43 ], and they may have a variety of other anticancer effects. The molecular mechanisms of antitumor and antiproliferative activity may be related to effects on the expression of biomolecules including Ras-MEK1/2, ERK1/2, the Wnt pathway, vascular endothelial growth factor, and β-catenin [ 44 ].…”