Article

Four cardiac hormones cause cell death in 81% of human ovarian adenocarcinoma cells

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Abstract

Summary Ovarian cancer has the highest mortality rate among all gynecological malignancies with an estimated 20,180 new cases and 15,310 deaths in the United States in 2006. Thus, for every four women diagnosed with ovarian cancer there were three deaths from ovarian cancer in 2006 in the United States. Four hormones synthesized by one gene in the heart i.e. atrial natriuretic peptide (ANP), vessel dilator, long acting natriuretic peptide (LANP), and kaliuretic peptide were evaluated with dose response (1 to 100 ∝M) experiments for the ability to decrease the number of human ovarian carcinoma cells in vitro and their DNA synthesis. There was an 81%, 74%, 71%, 70% and 53% increase in cancer cell death of ovarian adenocarcinoma cells within 24 hours secondary to vessel dilator, kaliuretic peptide, ANP, LANP, and their intracellular mediator cyclic GMP, respectively (each at 100 ∝M) (p

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... The four cardiac hormones from the ANP prohormone decrease up to 97% of human pancreatic, colon, prostate, breast, ovarian and kidney adenocarcinoma cells [26][27][28][29][30][31], angiosarcoma of the heart cells [32], melanomas [33], medullary thyroid carcinomas [34], glioblastomas of brain [35], as well as small-cell [36] and squamous cell lung carcinoma cells [37] in cell culture within 24 hours. There was a 97.4%, 87%, 88% and 89% (p < 0.001 for each) decrease of human prostate adenocarcinoma cells secondary to vessel dilator, long-acting natriuretic peptide, kaliuretic peptide, and atrial natriuretic peptide, respectively, within 24 hours at their 1 mM concentrations, without any proliferation in the three days following this decrease [28]. ...
... Vessel dilator, LANP, kaliuretic peptide and ANP inhibit DNA synthesis 80-91% in all human cancer cell lines [26][27][28][29][30][31][32][33][34][35][36][37]. Thus, after inhibiting ERK 1/2, DNA synthesis (a further or final step in the Ras-MEK 1/2-ERK 1/2 kinase pathway) is inhibited within the nucleus (Figure 4). ...
Article
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The heart is a sophisticated endocrine gland synthesizing the atrial natriuretic peptide prohormone which contains four peptide hormones, i.e., atrial natriuretic peptide, vessel dilator, kaliuretic peptide and long-acting natriuretic peptide, 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 in cell culture. In vivo, these four cardiac hormones eliminate up to 80% of human pancreatic adenocarcinomas, two-thirds of human breast cancers, and up to 86% of human small-cell lung cancers growing in athymic mice. Their signaling in cancer cells includes inhibition of up to 95% of the basal activity of Ras, 98% inhibition of the phosphorylation of the MEK 1/2 kinases and 97% inhibition of the activation of basal activity of the ERK 1/2 kinases mediated via the intracellular messenger cyclic GMP. They also completely block the activity of mitogens such as epidermal growth factor's ability to stimulate ERK and Ras. 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 immunocytochemical studies to inhibit DNA synthesis within cancer cells.
... In animals, peptides that possess anti-cancer activities are mainly found in the immune system, central nervous system, digestive system, heart, bone, muscle and skin [110]. Vesely et al. [111][112][113][114][115][116][117][118] investigated four types of cardiac natriuretic peptides, including atrial natriuretic peptide (ANP), vessel dilator peptide, long-acting natriuretic peptide (LANP) and kaliuretic peptide. These four peptides normally circulate in the human body and have shown anti-cancer activity against human cancers, including: pancreatic, breast, prostate, renal, colon, ovarian, melanoma, brain, thyroid and lung. ...
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Cancer along with cardiovascular disease are the main causes of death in the industrialised countries around the World. Conventional cancer treatments are losing their therapeutic uses due to drug resistance, lack of tumour selectivity and solubility and as such there is a need to develop new therapeutic agents. Therapeutic peptides are a promising and a novel approach to treat many diseases including cancer. They have several advantages over proteins or antibodies: as they are (a) easy to synthesise, (b) have a high target specificity and selectivity and (c) have low toxicity. Therapeutic peptides do have some significant drawbacks related to their stability and short half-life. In this review, strategies used to overcome peptide limitations and to enhance their therapeutic effect will be compared. The use of short cell permeable peptides that interfere and inhibit protein-protein interactions will also be evaluated.
... decrease of Wnt-3a in these cancer cell lines suggests that Wnt-3a is a target of the cardiac hormones in a variety of cancer cells. It is important to note that the decrease in Wnt-3a correlates with the decrease in cancer cell numbers in cell culture at the same concentrations as used in the present investigations (Vesely BA et al 2003, 2005a2006a,b;2007;Gower et al 2005). The cardiac hormones are efficacious over a concentration range of 100 pM to 10 μM (where their effects are usually strongest) in both decreasing cancer cell numbers and Wnt-3a concentration. ...
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The Wnt signaling pathway is a signal transduction pathway associated with oncogenesis in several human cancers. Four cardiac peptide hormones, namely vessel dilator, atrial natriuretic peptide (ANP), kaliuretic peptide, and long acting natriuretic peptide (LANP) have anticancer effects both in vitro and in vivo. These cardiac hormones were evaluated for their ability to inhibit Wnt-3a with a solid phase ELISA in human colorectal cancer cells, pancreatic carcinoma cells, and renal adenocarcinoma cells. In human pancreatic carcinoma cells, Wnt-3a was maximally decreased 66%, 66%, 68%, and 67% (each at p<0.0001) secondary to vessel dilator, kaliuretic peptide, ANP and LANP. Vessel dilator, kaliuretic peptide, ANP, and LANP maximally reduced the concentration of Wnt-3a by 53%, 52%, 53%, and 51% respectively (each at p<0.0001) in human colorectal adenocarcinoma cells. In human renal adenocarcinoma cells, Wnt-3a was maximally inhibited by vessel dilator, kaliuretic peptide, ANP, and LANP by 43%, 43%, 44%, and 42% (each at p<0.0001), respectively. This study indicates that four cardiac hormones are significant inhibitors (up to 68%) of Wnt-3a in human cancer cells as part of their anticancer mechanism(s) of action.
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Chapter
Host endocrine system is a complicated network of glands, that precisely secrete hormones, chemicals or peptides to regulate most, if not all host systemic activity. Although there has been hint on the effect of endocrine system in tumor growth, the in-depth mechanism remains ambiguous. In this chapter, not only we are looking at endocrine cancers and how these tumors can reciprocally dysregulate hormone production, more importantly, we are deciphering the effect of host endocrine system (i.e. age, metabolism, gender, etc.) towards solid tumor progression, solidifying our tumor ecosystem concept of host systemic influence on the local onco-sphere.
Chapter
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Article
Unlabelled: Four peptides synthesized in the heart, namely atrial natriuretic peptide (ANP), vessel dilator, kaliuretic peptide and long-acting natriuretic peptide (LANP), reduce cancer cells in vitro by up to 97%. These four cardiac hormones, in vivo, eliminate up to 86% of human small-cell lung carcinomas, two-thirds of human breast carcinomas, 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 triphosphate (RAS) (95% inhibition)-mitogen activated protein kinase kinase 1/2 (MEK-1/2) (98% inhibition)-extracellular signal-related kinases 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 their downstream targets of VEGF is β-Catenin, which they reduce up to 88%. The Wingless-related integration site (WNT) pathway is inhibited by up to 68% and WNT secreted-Frizzled related protein-3 was reduced by up to 84% by the four peptide hormones. A serine/threonine-protein kinase, AKT, derived from "AK" mouse strain with thymomas (T), is reduced by up to 64% by the peptide hormones. Signal transducer and activator of transcription 3 (STAT3), a final "switch" that activates gene expression patterns that lead to malignancy, is decreased by up to 88% by these peptide hormones; STAT3 is specifically reduced as they do not affect STAT1. There is cross-talk between the RAS-MEK-1/2-ERK-1/2 kinase cascade, VEGF, β-catenin, WNT, JNK and STAT pathways and each of these pathways is inhibited by the cardiac peptides. These peptides have been demonstrated to enter the nucleus of cancer cells where they inhibit the proto-oncogenes c-FOS (up to 82%) and c-JUN (up to 61%). Conclusion: The cardiac peptides inhibit multiple targets and cross-talk between the targets within cancer cells.
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β-Catenin causes malignant growth of colonic, pancreatic and renal cancer. Four cardiac hormones, namely atrial natriuretic peptide (ANP), vessel dilator, long-acting natriuretic peptide (LANP) and kaliuretic peptide eliminate up to 80% of human pancreatic carcinomas growing in mice. Four cardiac hormones were evaluated for their ability to reduce the expression of human β-catenin, measured by enzyme-linked immunosorbent assay (ELISA) in human colorectal, pancreatic and renal cancer cells. Vessel dilator, LANP, kaliuretic peptide, and ANP, over a concentration range of 100 pM to 10 μM, maximally reduced expression of β-catenin in human colorectal cancer cells by 78%, 71%, 69%, and 83%, respectively. Vessel dilator, LANP, kaliuretic peptide, and ANP reduced β-catenin expression in human pancreatic cancer cells by 76%, 66%, 72%, and 88%, and by 64%, 54%, 58% and 73%, in human renal cancer cells, respectively. Part of the anticancer action of these four cardiac hormones is a potent inhibition of β-catenin.
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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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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, 2/3rds 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 triphosphate (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 Beta-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. Signal transducer and activator of transcription 3 (STAT3), a final "switch" that activates gene expression that lead to malignancy, is decreased by up to 88% by the cardiac hormones. STAT3 is specifically decreased as they do not affect STAT1. There is 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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The heart is a sophisticated endocrine gland synthesizing the atrial natriuretic peptide (ANP) prohormone which contains four peptide hormones, namely atrial natriuretic peptide, vessel dilator, kaliuretic peptide and long-acting natriuretic peptide, 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 four cardiac hormones eliminate up to 80% of human pancreatic adenocarcinomas, up to two-thirds of human breast cancers, and up to 86% of human small-cell lung cancers in athymic mice. Their anticancer mechanism(s) target the Rat sarcoma bound guanosine triphosphate (RAS)-mitogen activated protein kinase kinase 1/2 (MEK1/2)-extracellular signal related kinase 1/2 (ERK1/2) kinase cascade in cancer cells. These four cardiac hormones inhibit up to 95% of the basal activity of Ras, 98% of the phosphorylation of MEK1/2 kinases and 96% of the activation of basal activity of ERK1/2 kinases. They also completely block the activity of mitogens such as the ability of epidermal growth factor to stimulate ERK and RAS. In addition to inhibiting these mitogen-activated protein kinases (MAPKs) they also inhibit MAPK9, i.e. c-Jun-N-terminal kinase 2. These multiple kinase inhibitors are cytotoxic and cause cell death of cancer cells but not of normal cells.
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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.
Article
Four cardiovascular hormones, ie, vessel dilator, long-acting natriuretic peptide, kaliuretic peptide, and atrial natriuretic peptide each at 1 mmol/L, decrease up to 97% of human breast, ovarian, pancreatic, colon, kidney, and prostate adenocarcinoma cells, as well as small cell and squamous cell lung cancer cells within 24 hours. Vessel dilator, long-acting natriuretic peptide, and kaliuretic peptide were investigated in vivo. These cardiac hormones completely stop the growth of human pancreatic adenocarcinomas in athymic mice and decrease their tumor volume by 49%, 28%, and 11%, respectively, in 1 week. When these cardiac hormones are given subcutaneously for 1 month via osmotic pumps with the pumps changed weekly, up to 80% of the human pancreatic adenocarcinomas growing in athymic mice can be completely eliminated. Similarly, two thirds of human breast cancers in athymic mice can be eliminated without surgery with these cardiac hormones. Natriuretic peptide receptors A-, B-, and C- are present on the cancer cells to mediate atrial natriuretic peptide's effects. The cardiac hormones' anticancer mechanism of action(s) include a strong inhibition of mitogen (epidermal growth factor and insulin) activated extracellular signal-regulated kinases (ERK) 1/2 and as well as inhibition of basal extracellular-signal regulated kinase 1/2 and upstream MEK 1/2 phosphorylation. They cause 80% to 90% inhibition of DNA synthesis in the nucleus where these cardiac hormones have been demonstrated to localize by immunocytochemical techniques.
Article
Atrial natriuretic peptide and long acting natriuretic peptide have anticancer effects in human prostate adenocarcinomas. Atrial natriuretic peptide, long acting natriuretic peptide and cyclic GMP's effects on MEK 1/2 kinase were examined in human prostate adenocarcinoma cells. Atrial natriuretic peptide and long acting natriuretic peptide decreased the activation of MEK 1/2 over a concentration range of 0.01 microM to 10 microM. Long acting natriuretic peptide and atrial natriuretic peptide (each 10 microM) inhibited the phosphorylation of MEK 1/2 kinase 97% (p < 0.00001) and 88% (p < 0.00001), respectively. The inhibition of MEK 1/2 was maximal at two hours, and ceased by four hours, secondary to both peptides. The ability of peptides to inhibit MEK 1/2 was inhibited by cyclic GMP antibody and cyclic GMP itself inhibited MEK 1/2 phosphorylation by 93%. Atrial natriuretic peptide and long acting natriuretic peptide both inhibit MEK 1/2 kinase mediated via cyclic GMP as part of their anticancer mechanism(s) of action.
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