Cardiac hormones for the treatment of cancer

Abstract

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.

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

“…This is supported by the co-localization of ANP and the Frizzled receptor observed on membrane of treated cells as well as by the evidences demonstrating the ability of ANP and Wnt1a in competing and displacing each other from the binding receptor [30]. Our results were sustained by data obtained by Vesely and collaborators, demonstrating that ANP and the other natriuretic hormones LANP, VSDL and KP are able to decrease the concentration of β-catenin up to 88% in human pancreatic cancer cells, up to 83% in human colorectal adenocarcinoma cells, and up to 73% in human renal adenocarcinoma cells [31]. The same Authors also reported that, in pancreatic, colorectal and renal cancer cells, all the four cardiac hormones reduce the concentration of the Wnt pathway activator WNT-3a [31] and decrease the levels of the Secreted Frizzled-related protein-3 (sFRP-3) [39], a secreted glycoprotein that affects Wnt signaling and that has been linked to tumor promotion in different types of cancers [40].…”

“…This innovative aspect of ANP anticancer efficacy, is partially sustained by the results obtained by Vesely and collaborators, that demonstrated its effect on some components of the Wnt signaling [31]. …”

Tumor Specific Hypoxia-Activated Expression of Cardiac Peptides Using an Engineered Subtype of Escherichia Coli Suppresses Tumor Growth, Angiogenesis and Metastasis in Mouse Model of Breast Cancer

“…Several in vitro studies have clearly indicated the cytotoxic effects of cardiac peptides against malignant cells. Based on studies performed by Vesely et al, four cardiac peptides including LANP, KP, VD and ANP demonstrate signi cant anti-proliferative effects against breast, prostate, lung, brain and renal carcinomas (Vesely, 2013). Reported by Sun et al, VD and KP demonstrate their anti-cancer activities in prostate cancer through inhibiting RAS activity (Sun et al, 2010).…”

Subcutaneous pharmacokinetics of the cardiac hormone vessel dilator

“…Vessel dilator blocks the cycle (Fig. ) by which these kinases and β ‐catenin stimulate each other to cause cancer cells to grow . The in vivo anticancer effects of vessel dilator described above were observed after s.c. infusion (ScI), but the pharmacokinetics of vessel dilator after ScI have not been determined.…”

“…Vessel dilator eliminates 33% of human pancreatic adenocarcinomas growing in mice when it is given s.c . The mechanism of action of vessel dilator within cancer cells involves multiple targets (Fig. ).…”