Professor 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.
Anticancer Res. 2014 Apr;34(4):1459-66.
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%).
The cardiac peptides inhibit multiple targets and cross-talk between the targets within cancer cells.
四种在心脏中合成的肽，即心钠肽 (ANP)、血管扩张剂、利钾肽和长效利钠肽 (LANP)，在体外可使癌细胞减少多达 97%。这四种心脏激素在体内可消除多达 86%的人小细胞肺癌、三分之二的人乳腺癌和多达 80%的人胰腺腺癌在无胸腺小鼠中生长。它们的抗癌作用机制包括与癌细胞上的特定受体结合后，靶向 Rat sarcoma-bound guanosine triphosphate (RAS)（95%抑制）-mitogen activated protein kinase kinase 1/2 (MEK-1/2)（98%抑制）-extracellular signal-related kinases 1/2 (ERK-1/2)（96%抑制）级联反应。它们还抑制 MAPK9，即 c-JUN-N-terminal kinase 2。它们是血管内皮生长因子 (VEGF) 及其 VEGFR2 受体的双重抑制剂（高达 89%）。它们的 VEGF 的一个下游靶标是β-Catenin，可将其减少多达 88%。Wingless 相关整合位点 (WNT) 途径被抑制多达 68%，WNT 分泌的 Frizzled 相关蛋白-3 被四种肽激素减少多达 84%。一种丝氨酸/苏氨酸蛋白激酶 AKT，来自于带有胸腺瘤 (T) 的“AK”小鼠品系，被肽激素减少多达 64%。信号转导和转录激活因子 3 (STAT3)，一种激活导致恶性肿瘤的基因表达模式的最终“开关”，被这些肽激素降低多达 88%；STAT3 被特异性降低，因为它们不影响 STAT1。RAS-MEK-1/2-ERK-1/2 激酶级联反应、VEGF、β-Catenin、WNT、JNK 和 STAT 途径之间存在串扰，并且这些途径中的每一种都被心脏肽抑制。已经证明这些肽进入癌细胞的细胞核，在那里它们抑制原癌基因 c-FOS（高达 82%）和 c-JUN（高达 61%）。
心脏肽抑制癌细胞内的多个靶标和靶标之间的串扰。
