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New Anticancer Agents: Hormones Made Within the Heart

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New Anticancer Agents: Hormones Made Within the Heart ANTICANCER RESEARCH 32: 2515-2522 (2012) Review New Anticancer Agents: Hormones Made within the Heart DAVID L. VESELY Departments of Medicine, Molecular Pharmacology and Physiology, and Cardiac Hormone Center, James A. Haley VA Medical Center, and University of South Florida Morsani School of Medicine, Tampa, FL, U.S.A. Abstract. The heart is a sophisticated endocrine gland involved in blood pressure regulation and maintenance of synthesizing the atrial natriuretic peptide (ANP) plasma volume in animals (4-9) and humans (10-12). These prohormone which contains four peptide hormones, namely cardiac hormones, numbered by their a.a. sequences atrial natriuretic peptide, vessel dilator, kaliuretic peptide beginning at the N-terminal end of the atrial natriuretic and long-acting natriuretic peptide, which decrease up to peptide (ANP) prohormone, consist of the first 30 a.a. of the 97% of human pancreatic, breast, colon, prostate, kidney prohormone, namely, long-acting natriuretic peptide (LANP), and ovarian carcinomas, as well as small-cell and a.a. 31-67 (namely, vessel dilator), a.a. 79-98 (kaliuretic squamous cell lung cancer cells within 24 hours in cell peptide) and a.a. 99-126 (ANP) (13, 14). Each of these culture. In vivo these four cardiac hormones eliminate up to peptide hormones circulates in healthy humans, with the 80% of human pancreatic adenocarcinomas, up to two- concentrations of vessel dilator and LANP in plasma being thirds of human breast cancers, and up to 86% of human 17- to 24-fold higher than that of ANP (15-20). small-cell lung cancers in athymic mice. Their anticancer mechanism(s) target the Rat sarcoma bound guanosine Heart Hormones Eliminate up to triphosphate (RAS)-mitogen activated protein kinase kinase 97% of Cancer Cells In Vitro 1/2 (MEK1/2)-extracellular signal related kinase 1/2 (ERK1/2) kinase cascade in cancer cells. These four cardiac The four cardiac hormones reduce up to 97% of human hormones inhibit up to 95% of the basal activity of Ras, pancreatic, colon, prostate, breast, ovarian and kidney 98% of the phosphorylation of MEK1/2 kinases and 96% of adenocarcinoma cells (21-26), angiosarcoma of the heart the activation of basal activity of ERK1/2 kinases. They also cells (27), melanomas (28), medullary thyroid carcinomas completely block the activity of mitogens such as the ability (29), glioblastomas of the brain (30), as well as small-cell of epidermal growth factor to stimulate ERK and RAS. In (31) and squamous cell lung carcinoma cells (32) in cell addition to inhibiting these mitogen-activated protein culture. There is a 97.4%, 87%, 88% and 89% (p<0.0001 for kinases (MAPKs) they also inhibit MAPK9, i.e. c-Jun-N- each) decrease (namely, elimination) of human prostate terminal kinase 2. These multiple kinase inhibitors are adenocarcinoma cells by vessel dilator, LANP, kaliuretic cytotoxic and cause cell death of cancer cells but not of peptide, and ANP, respectively, within 24 hours at their 1 normal cells. mM concentrations (23). There is no proliferation in the three days following this decrease, induced by the heart The heart is a sophisticated endocrine gland synthesizing a hormones (23). When antibodies to these four cardiac 126 amino acid (a.a.) prohormone which contains four hormones are used, the ability of the hormones to reduce the peptide hormones (1-3). These peptide hormones are number of prostate cancer cells is completely blocked, indicating that their effects are specific, namely not due to some other hormone or substance (23). Dose response curves have revealed that there is a significantly greater (p<0.05) Correspondence to: David L. Vesely, MD, PhD, James A. Haley decrease in the number of cancer cells at each 10-fold Veterans Hospital (151), 13000 Bruce B. Downs Blvd., Tampa, Florida 33612, U.S.A. Tel: +1 8139727624, Fax: +1 8139727623, increase in the concentration of the four cardiac hormones e-mail: david.vesely@va.gov synthesized by the ANP gene in human breast, colon and prostate cancer cells as well as in small-cell and squamous Key Words: Cancer, natriuretic peptides, metastasis, review. cell carcinoma of lung cells (21-26, 31, 32). 0250-7005/2012 $2.00+.40 2515 ANTICANCER RESEARCH 32: 2515-2522 (2012) Table I. Ability of cardiac hormones to eliminate human cancer growing in athymic mice. The numbers in each column are the percentages of human carcinomas eliminated and which never recurred in the primary site in athymic mice, when treated with each of the cardiac hormones for 28 days at 3 nM/kg body weight/minute. VDL, Vessel dilator; LANP, long acting natriuretic peptide; ANP, atrial natriuretic peptide; KP, kaliuretic peptide. Breast Pancreatic Small-cell cancer adenocarcinoma lung cancer VDL 67% 33% 71% LANP 50% 20% 86% ANP 33% 80% 43% KP 67% 14% 57% Figure 1. The atrial natriuretic peptide (ANP) gene in the heart, codes for a 126 amino acid (a.a.) prohormone which through proteolytic processing results in the formation of four cardiac hormones. These four cardiac hormones are: long-acting natriuretic peptide (LANP) consisting of the first 30 a.a. of the 126 a.a. prohormone; vessel dilator (VDL), a.a. 31-67 of the prohormone; kaliuretic peptide (KP), a.a. 79- Heart and Kidney Hormones Eliminate up 98 of this prohormone; and ANP, consisting of a.a. 99-126 of the 126 to 86% of Human Small-Cell Lung a.a. prohormone. Reprinted with permission from reference 47. Carcinomas in Mice LANP, vessel dilator, KP, and ANP eliminate 86%, 71%, 57%, 43% (p<0.001 for each) of human small-cell lung carcinomas (36). Treated small-cell lung carcinomas that are Heart Hormones Eliminate up to 80% of not eliminated grow rapidly, similar to the untreated Human Pancreatic Adenocarcinomas In Vivo controls, whose volume is 7-fold larger in one week, 18-fold increased in two weeks, 39-fold increased in three weeks, Human pancreatic adenocarcinoma has the lowest 5-year 63-fold increased in one month and 97-fold increased in survival rate of all common types of cancers (33, 34). The 5- volume in six weeks (36). One vessel dilator-treated animal year survival rate of patients with adenocarcinoma of the with small-cell lung carcinoma developed a large tumor pancreas is 1%, with a median survival of only four months (8,428 mm3 volume) upon treatment and this tumor was (33, 34). Current cancer chemotherapy and surgery prolong eliminated utilizing ANP and then LANP, each for four survival by a few months, but the mean survival of four weeks sequentially (36). months, refers to patients who were treated with surgery and/or current cancer chemotherapeutic agents (33, 34). Heart Hormones Eliminate Two-Thirds of When each of the heart hormones are infused Human Breast Carcinomas without any Surgery subcutaneously at 3 nM min–1 kg–1 body weight for 28 days in athymic mice bearing human pancreatic adenocarcinomas, Vessel dilator, LANP, KP and ANP eliminate 67%, 50%, 67% ANP eliminated 80% of the human pancreatic carcinomas and 33% of the human breast adenocarcinomas in athymic (35). Vessel dilator, LANP and KP eliminated the primary mice, when infused subcutaneously for 28 days, with fresh pancreatic carcinomas by 33%, 20%, and 14% in their hormones prepared weekly at 3 nM min–1 kg–1 body weight respective treatment groups (35). In none of the animals in (37). There was no recurrence of the breast cancer at the which the pancreatic adenocarcinomas are eliminated in the primary site and no metastasis, except in the ANP-treated primary site, does a single animal ever have a recurrence in group (37). The natriuretic peptide receptors A and C were the primary site (35). One ANP-treated animal developed a decreased 50% and 31%, respectively, in metastatic versus metastatic lesion and this lesion was eliminated by treatment primary ANP-treated breast adenocarcinomas, possibly with vessel dilator (35). Even in the treated animals which explaining why fewer of the breast carcinomas responded to did not have total elimination of their human pancreatic ANP compared to the other three cardiac hormones, as ANP adenocarcinoma with the four respective heart hormones, works via these receptors while the other peptide hormones tumor volumes decreased to less than 10% (and with vessel have their own specific receptors (2, 3, 37). Thus, the four dilator to less than 2%) compared to those of the untreated hormones made within the heart have the ability to eliminate animals, both during treatment and in a 12-month follow-up human pancreatic, breast and small-cell lung cancer growing period (35). in mice but their respective abilities to eliminate these 2516 Vesely et al: Cardiac Hormones: Anticancer Agents (Review) Figure 2. Cardiac hormones inhibit five metabolic targets, namely RAS-GTP, MEK1/2, and ERK1/2 of the RAS-MEK1/2-ERK1/2 kinase cascade by 95-98%. These multiple kinase inhibitors are also strong inhibitors (i.e. 91%) of DNA synthesis within cancer cells. Abbreviations: Tyrosine kinase receptor (RTK); Rous sarcoma viral proto-oncogene tyrosine kinase (SRC); Rous sarcoma SH2 C-terminal binding domain adapter protein (SHC); Growth factor receptor-bound protein 2 (GRB2); Son of Sevenless gene (SOS); rat sarcoma bound guanosine diphosphate (RAS-GDP); Rat sarcoma bound guanosine triphosphate (RAS-GTP); Rapidly accelerated fibrosarcoma serine/threonine protein kinase (RAF); Maloney murine sarcoma virus serine/threonine protein kinase (MOS); Mitogen-activated protein kinase kinase 1/2 (MEK1/2); extracellular signal-related kinases 1/2 (ERK1/2); Protein phosphatase 2A (PP2A); Deoxyribonucleic acid (DNA). Reprinted with permission from reference 44. different types of cancers varies with the type of cancer, as Metabolic Targets of Heart Hormones within illustrated in Table I. Cancer Cells Mechanism of Action of Heart After binding to their respective receptors on the cancer Hormones: Receptors cells, the cardiac hormones inhibit the RAS mitogen- activated protein kinase (MAPK)/extracellular signal-related Each of the human cancer cell types examined above has kinase-kinase (MEK)-ERK1/2 kinase pathway (Figure 2), natriuretic peptide receptors to mediate the effects of these which is a prototypical signal transduction pathway in cancer peptide hormones (21-32).
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