atrial-natriuretic-factor and Colorectal-Neoplasms

The aim of this single center, non-randomized, open-label, uncontrolled, interventional trial was to determine the feasibility of continuous administration of low-dose human atrial natriuretic peptide (hANP) perioperatively during curative operation for colorectal cancer patients without history of acute heart failure.. The study included three males and two females ranging from 27 to 70 years old. Continuous intravenous injection of hANP solution was started before surgery. The primary endpoint was safety of hANP administration, and the secondary endpoints were perioperative changes in ANP, b-type natriuretic peptide, electrocardiogram (ECG), and lung function.. The American Society of Anaesthesiologists physical status was 1, 2, and 3 in three, one, and one patient, respectively. Grade 2 hypotension was observed in one case. No marked changes were observed between pre- and post-operation in all cases.. Perioperative low-dose hANP administration is feasible and safe in patients with curative colorectal cancer.

Topics: Adult; Aged; Atrial Natriuretic Factor; Biomarkers; Colorectal Neoplasms; Electrocardiography; Female; Heart Failure; Humans; Male; Middle Aged; Neoplasm Staging; Perioperative Care; Postoperative Complications; Symptom Assessment; Treatment Outcome

Hypertension is a common early adverse event of anti-angiogenic treatment of cancer and may associate with treatment response. However, blood pressure measurement as a surrogate response biomarker has methodological limitations, and predictive biomarkers of angiogenesis inhibitors are lacking. In disease associated with hypertension, vasoactive peptides have been linked to cardiovascular pressure load. Here, we have explored potential associations between circulating levels of vasoactive peptides and tumor response during bevacizumab-containing treatment of colorectal cancer.. Metastatic colorectal cancer (mCRC) patients with available best objective response (ORR) and time to tumor progression (TTP) data were included from a randomized clinical trial investigating maintenance therapy after first line chemotherapy plus bevacizumab. Midregional-pro-adrenomedullin (MR-proADM), midregional-pro-atrial-natriuretic-peptide (MR-proANP), and C-terminal-prepro-vasopressin (Copeptin) vasoactive peptide concentrations were measured in plasma at baseline and after 6 weeks of chemotherapy and bevacizumab treatment (n = 97). We determined associations among clinical outcome (ORR and TTP), peptide levels, and hypertension (NCI-CTCAE 4.0 criteria), using Spearman's test, multiple linear regression, and Mann-Whitney's test.. Increasing levels of vasoactive peptides from baseline and after six weeks of treatment were associated with improved treatment outcome (MR-proADM: ORR, p = .0003; TTP, p = .05; MR-proANP: ORR, p = .05; TTP, p = .03; Copeptin: ORR, p = .10; TTP, p = .02). Patients with increasing levels of all three peptides (n = 28) versus increasing levels of one or two peptides (n = 59) showed a median TTP of 284 and 225 d, respectively (p = .02).. Our results suggest that increasing systemic levels of vasoactive peptides associate with improved tumor response and TTP in mCRC patients treated with a bevacizumab-containing regimen. These findings support the proposed link between the tumor vasculature and the cardiovascular system of the host. This should motivate further studies that investigate the potential role of vasoactive peptides as a novel class of dynamic biomarkers in the treatment of cancer.

Topics: Adrenomedullin; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Atrial Natriuretic Factor; Biomarkers, Tumor; Colorectal Neoplasms; Female; Follow-Up Studies; Glycopeptides; Humans; Lymphatic Metastasis; Male; Middle Aged; Prognosis; Protein Precursors; Survival Rate

Vessel dilator is a 3.9-KDa potent anticancer peptide and a valuable candidate in the treatment of conditions such as congestive heart failure and acute renal failure amongst others. Here we report the recombinant production of vessel dilator in Escherichia coli. Three different synthetic ORF's dubbed VDI, VDII and VDIII, each encoding a trimmer of the vessel dilator peptide attached to a His tag sequence at their C- terminal, were synthesized and placed in pET21c expression vectors. The highest yield, following expression in E. coli BL21 (DE3), was recorded with VDII that carried the shortest fusion partner. Subsequent to the initial capture of the fusion protein by a Ni affinity column, the vessel dilator monomers were cleaved by trypsin treatment, and further purified to at least 90% homogeneity by anion exchange chromatography. De-novo sequencing and in vivo anticancer activity tests were used to verify the peptide sequence and its biological activity, respectively. The final yield was estimated to be approximately 15 mg of the purified vessel dilator per gram wet weight of the bacterial cells.

Topics: Antineoplastic Agents; Atrial Natriuretic Factor; Cell Line, Tumor; Chromatography, Affinity; Colorectal Neoplasms; Escherichia coli; Histidine; Humans; Peptide Fragments; Recombinant Fusion Proteins

Protein kinase-B (AKT) is a serine/threonine protein kinase that has a key role in cell proliferation and cancer cell invasiveness. 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.. Four cardiac hormones were examined for their ability to inhibit AKT, measured with a solid-phase enzyme-linked immunosorbent assay (ELISA) in human colorectal, pancreatic, and renal cancer cells.. Vessel dilator, kaliuretic peptide, ANP, and LANP maximally reduced the concentration of AKT by 47%, 45%, 52%, and 46% in human colorectal cancer cells (p<0.0001), by 60%, 61%, 64%, and 59% in human pancreatic carcinoma cells (p<0.0001), and by 31%, 32%, 31%, and 31% in renal adenocarcinoma cells (p<0.001).. These four cardiac hormones are significant inhibitors of AKT in human cancer cells, as part of their anticancer mechanism(s) of action.

Topics: Adenocarcinoma; Antineoplastic Agents; Atrial Natriuretic Factor; Cell Line, Tumor; Colorectal Neoplasms; Humans; Kidney Neoplasms; Pancreatic Neoplasms; Peptide Fragments; Protein Precursors; Proto-Oncogene Proteins c-akt

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.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Atrial Natriuretic Factor; beta Catenin; Cell Line, Tumor; Colonic Neoplasms; Colorectal Neoplasms; Humans; Kidney Neoplasms; Mice; Pancreatic Neoplasms; Peptide Fragments; Protein Precursors

Acidic tumor microenvironment and Wnt/β-catenin pathway activation have been recognized as two crucial events associated with the initiation and progression of cancer. The aim of this study was to clarify the molecular mechanisms underlying the anti-proliferative effects of atrial natriuretic peptide (ANP) as well as to investigate the relationship between the cellular pH and the Wnt/β-catenin signaling in cancer cells.To pursue our aims, we conducted investigations in DHD/K12/Trb rat colon adenocarcinoma cells. Intracellular pH was measured by Confocal Laser Scanning Microscopy (CLSM) using the lysosensor Green DND-189 probe. Expression of crucial molecules in the Wnt/β-catenin signaling pathway was analyzed by CLSM, western blot, and real time PCR. Measurements of activation (phosphorylation state) of Akt, ERK1/2, and p38MAPKinase were performed by Reverse-Phase Protein Microarray Analysis (RPMA).We showed that ANP triggered a NHE-1-mediated increase of the intracellular acidity, inhibiting the Wnt/β-catenin signaling simultaneously. Moreover, we observed that the Wnt1a, a Wnt signaling activator, affected the intracellular pH in an opposite fashion. Results from the comparative analysis of ANP and EIPA (a NHE-1 specific inhibitor) showed that these two molecules affect both the intracellular acidification and the Wnt/β-catenin signaling cascade. Specifically, ANP acts on the upstream of the cascade, through a Frizzled-mediated activation, while EIPA does on the downstream.We show for the first time that the Akt activity might be a relevant molecular event linking the NHE-1-regulated intracellular pH and the Wnt/β-catenin signaling. This provides evidence for a cross-talk between the intracellular alkalinization and the Wnt signaling in tumor cells.

Topics: Adenocarcinoma; Amiloride; Animals; Atrial Natriuretic Factor; beta Catenin; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Hydrogen-Ion Concentration; MAP Kinase Signaling System; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Sodium-Hydrogen Exchanger 1; Sodium-Hydrogen Exchangers; Wnt Signaling Pathway