Heart Peptide Hormones: Adjunct and Primary Treatments of Cancer
1Departments of Medicine, Molecular Pharmacology and Physiology, University of South Florida Morsani School of Medicine, Tampa, FL, U.S.A. david.tampabay@gmail.com.
Abstract:
Four heart hormones, namely atrial natriuretic peptide (ANP), long-acting natriuretic peptide (LANP), vessel dilator and kaliuretic peptide reduce up to 97% of cancer cells in vitro. These four cardiac hormones eliminate up to 80% of human pancreatic adenocarcinomas, two-thirds of human breast carcinomas and up to 86% of human small-cell lung carcinomas growing in athymic mice. ANP given intravenously for 3 hours after 'curative' lung surgery as an adjunct to surgery results in a 2-year relapse-free survival of 91% compared to 75% for those treated with surgery alone. The anticancer mechanisms of action of these peptides involve binding to receptors on the cancer cells, followed by 95% inhibition of the conversion of inactive to active rat sarcoma-bound guanosine triphosphate (RAS)-mitogen-activated protein kinase (MAPK) kinases 1/2 (MEK 1/2) (98% inhibition)-extracellular signal-related kinases 1/2 (ERK1/2) (96% inhibition) cascade in cancer cells. They are dual inhibitors of vascular endothelial growth factor (VEGF) and its VEGF2 receptor (up to 89%). They also inhibit MAPK9, i.e. c-JUN-N-terminal kinase 2. One of the downstream targets of VEGF is β-catenin, which these peptides inhibit by up to 88%. These four peptide hormones inhibit the Wingless-related integration site (WNT) pathway 68% and WNT secreted-Frizzled protein is reduced by up to 84%. Signal transducer and activator of transcription 3 (STAT3), a final 'switch' that activates gene expression that leads to malignancy, is specifically reduced up to 88% by these peptides but they do not affect STAT1. There is crosstalk between the RAS-MEK 1/2-ERK 1/2 kinase cascade, VEGF, β-catenin, JNK, WNT, and STAT pathways and each of these pathways and their crosstalk is inhibited by these peptide hormones. They enter the nucleus of cancer cells where they inhibit the proto-oncogenes c-FOS (by up to 82%) and c-JUN (by up to 61%).
Conclusion:
These multiple kinase inhibitors have both adjunct and primary anticancer effects.
Insights
Four heart hormones significantly reduce cancer cells in vitro and in vivo. These peptides enhance relapse-free survival after lung surgery by inhibiting key cancer pathways.
Area of Science:
- Cardiovascular Endocrinology
- Oncology
- Molecular Biology
Background:
- Cardiac hormones, including atrial natriuretic peptide (ANP), long-acting natriuretic peptide (LANP), vessel dilator, and kaliuretic peptide, have demonstrated potential in cancer research.
- Understanding the molecular mechanisms by which these hormones exert anticancer effects is crucial for therapeutic development.
Purpose of the Study:
- To investigate the anticancer efficacy of four specific heart hormones.
- To elucidate the molecular pathways targeted by these hormones in cancer cells.
- To evaluate the potential of these hormones as adjunct therapy in cancer treatment.
Main Methods:
- In vitro and in vivo studies using various cancer cell lines and human tumor xenografts in athymic mice.
- Intravenous administration of ANP in a clinical setting following lung surgery.
- Analysis of molecular signaling pathways including RAS-MEK-ERK, VEGF, WNT, and STAT3.
Main Results:
- These four cardiac hormones reduced cancer cells by up to 97% in vitro and demonstrated significant efficacy against pancreatic, breast, and lung carcinomas in mice.
- ANP administration post-lung surgery improved 2-year relapse-free survival from 75% to 91%.
- The hormones inhibit key cancer-promoting pathways, including RAS-MEK-ERK, VEGF, WNT, and STAT3, and nuclear proto-oncogenes c-FOS and c-JUN.
Conclusions:
- The studied cardiac hormones possess significant primary and adjunct anticancer properties.
- These peptides represent a novel class of multiple kinase inhibitors with broad-spectrum anticancer activity.
- Further clinical investigation of these heart hormones as cancer therapeutics is warranted.
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