Metabolic targets of cardiac hormones' therapeutic anti-cancer effects.
The heart is a sophisticated endocrine gland synthesizing a family of peptide hormones by three different genes. These cardiac hormones are stored as 3 prohormones, i.e. atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) prohormones. Within the ANP prohormones are 4 peptide hormones, i.e. atrial natriuretic peptide, vessel dilator, kaliuretic peptide and long-acting natriuretic peptide (LANP) which decrease up to 97% of human pancreatic, breast, colon, prostate, kidney and ovarian carcinomas as well as small-cell and squamous cell lung cancer cells within 24 hours in cell culture. In vivo these 4 cardiac hormones eliminate up to 80% of human pancreatic adenocarcinomas, 2/3rds of human breast cancers, and up to 86% of human small-cell lung cancers in athymic mice. Their anticancer mechanism(s) target the Ras-MEK 1/2-ERK 1/2 kinase cascade in cancer cells. These 4 cardiac hormones inhibit up to 95% of the basal activity of Ras, 98% of the phosphorylation of MEK 1/2 and 97% of the activation of basal activity of ERK 1/2. They also completely block the activity of mitogens such as epidermal growth factor's ability to stimulate ERK. They do not inhibit the activity of ERK in healthy cells such as human fibroblasts. The final step in their anticancer mechanism of action is that they enter the nucleus as demonstrated by immunfluorescence to inhibit DNA synthesis within cancer cells.
Vesely
David L
DL
Departments of Medicine, Molecular Pharmacology and Physiology, and Cardiac Hormone Center, James A. Haley Veterans Medical Center and University of South Florida Health Sciences Center, Tampa, Florida 33612, USA. david.vesely@va.gov
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D009320:Atrial Natriuretic Factor / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017461:Receptors, Atrial Natriuretic Factor / Q000819:agonists; D015398:Signal Transduction / Q000187:drug effects*
D018931:Antineoplastic Agents, Hormonal; D009320:Atrial Natriuretic Factor; D004247:DNA; D017461:Receptors, Atrial Natriuretic Factor