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1Professor of Internal Medicine, Molecular Pharmacology and Physiology, Director, USF Cardiac Hormone Center, University of South Florida Morsani School of Medicine, Tampa, FL - 33612, U.S.A. J.A. Haley VA Medical Center-151, 13000 Bruce B. Downs Blvd., Tampa, FL - 33612, U.S.A. david.tampabay@gmail.com.
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.
Insights
Four cardiac peptides show significant anticancer effects, reducing various human carcinomas in mice. These peptides target multiple signaling pathways within cancer cells, offering a novel therapeutic approach.
Area of Science:
- Cardiovascular endocrinology
- Oncology
- Molecular biology
Background:
- Cardiac hormones, including atrial natriuretic peptide (ANP), vessel dilator, kaliuretic peptide, and long-acting natriuretic peptide (LANP), are synthesized in the heart.
- Cancer cells exhibit dysregulated signaling pathways crucial for their proliferation and survival.
Purpose of the Study:
- To investigate the in vitro and in vivo anticancer efficacy of four cardiac peptides.
- To elucidate the molecular mechanisms underlying the anticancer activity of these peptides.
Main Methods:
- In vitro and in vivo studies using human cancer cell lines and tumor xenografts in athymic mice.
- Analysis of peptide interactions with specific cancer cell receptors and inhibition of key signaling pathways.
Main Results:
- Cardiac peptides reduced cancer cells in vitro by up to 97% and eliminated up to 86% of human small-cell lung carcinomas, 67% of breast carcinomas, and 80% of pancreatic adenocarcinomas in vivo.
- Peptides inhibited the RAS-MEK-1/2-ERK-1/2 cascade (up to 98%), MAPK9, VEGF/VEGFR2 (up to 89%), β-catenin (up to 88%), WNT pathway (up to 68%), AKT (up to 64%), and STAT3 (up to 88%).
- Inhibition of proto-oncogenes c-FOS (up to 82%) and c-JUN (up to 61%) within the cancer cell nucleus was observed.
Conclusions:
- Cardiac peptides exhibit potent anticancer activity through multifaceted inhibition of critical cancer signaling pathways.
- These peptides represent a promising therapeutic strategy targeting multiple oncogenic pathways simultaneously.
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