atrial-natriuretic-factor and Breast-Neoplasms

Atrial natriuretic peptides (ANPs) consist of a family of six peptide hormones that are synthesized by three different genes and then stored as three different prohormones. Within the 126-amino acid ANP prohormone are four peptide hormones: long-acting natriuretic peptide (LANP), vessel dilator, kaliuretic peptide, and ANP, whose main known biologic properties are blood pressure regulation and maintenance of plasma volume. The newest discovered property of these peptide hormones is their anticancer effects. Vessel dilator, LANP, kaliuretic peptide, and ANP decrease the number of human pancreatic adenocarcinoma cells in culture by 65%, 47%, 37%, and 34%, respectively, within 24 hours at their 1 microM concentrations. Similar results have been found with breast adenocarcinomas, squamous cell lung cancer, and small cell lung cancer cells, each associated with an 83% or greater inhibition of deoxyribonucleic acid (DNA) synthesis by these four peptide hormones. Brain natriuretic peptide has no effects even when increased 100-fold (ie, 100 microM). C-type natriuretic peptide has no effects when increased 10-fold, but when increased 100-fold, it decreases 39% of the cancer cells. At this higher 100 microM concentration, vessel dilator kills 92% of the cancer cells within 24 hours. The four peptide hormones synthesized by the ANP gene given subcutaneously via osmotic pumps in athymic mice with human pancreatic adenocarcinomas completely stop the growth of these adenocarcinomas at 1 week. Vessel dilator, LANP, and kaliuretic peptide within 1 week decrease the volume by 49%, 28%, and 11% of the human pancreatic adenocarcinomas, which, with current anticancer treatment, have a mean survival of only 4 months.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Atrial Natriuretic Factor; Breast Neoplasms; Cell Line, Tumor; DNA, Neoplasm; Female; Humans; Mice; Pancreatic Neoplasms

Cardiac function impairment is a known side effect of epirubicin-based chemotherapy. Activation of natriuretic peptides is demonstrated in patients with heart failure.. To identify prospectively the cardiotoxic profile of epirubicin-based chemotherapy in breast cancer patients and to evaluate the sensitivity of proANP and NT-proBNP as early biochemical markers of cardiac dysfunction.. Forty cancer patients divided in two nonrandomized groups received either epirubicin and paclitaxel (Group A, n=26) or mitoxantrone and docetaxel (Group B, n=14). Control groups, Group C (n=13) and Group D (n=20), consisted of female patients with heart failure and healthy women respectively. Natriuretic peptides and LVEF were determined in all patients.. A statistically significant difference was recorded regarding LVEF before and after treatment in Group A patients (p=0.0001). Three patients had a significant LVEF decline between 10% and 18% from baseline values, while three reached an LVEF value below 50%. All of them presented an increase in proANP and NT-proBNP values (mean increase 270.31+/-124 fmol/ml and 303.57+/-108 fmol/ml, respectively). A significant correlation between the increase in plasma proANP (r=0.8, p<0.0001), as well as NT-proBNP (r=0.7, p<0.0001) and the decrease in LVEF was observed. Regarding Group A, levels of proANP increased from 192.25 fmol/ml before treatment to 287.84 fmol/ml after treatment (p=0.0001), whereas NT-proBNP increased from 152.50 to 242 fmol/ml (p<0.0001) respectively. During follow up, two Group A patients developed congestive heart failure twelve and fourteen months after the completion of chemotherapy respectively. A significant LVEF decline was recorded in both patients during the episode. Regarding Group B, no statistically significant differences were demonstrated.. ProANP and NT-proBNP levels might be used as reliable and sensitive markers in the detection of early cardiac impairment caused by epirubicin-based chemotherapy.

Topics: Adult; Antineoplastic Agents; Atrial Natriuretic Factor; Biomarkers; Breast Neoplasms; Cardiovascular Diseases; Female; Humans; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prospective Studies; Protein Precursors

The atrial natriuretic factor (ANF) plays an important role in the pathogenesis of congestive heart failure (CHF), by influencing electrolyte and water balance and by modifying peripheral vascular resistance, thus affecting left ventricular performance. Anthracycline derivatives are glycoside antibiotics, active against a wide spectrum of tumours. It is well known that acute and severe dose-related delayed cardiotoxicity constitutes the major limitation to their optimal use. A total of 26 female patients (mean age 53 years) undergoing monochemotherapy for advanced breast cancer, were studied. 4'-Epidoxorubicin (Epidx) 120 mg/m2 intravenously was administered every three weeks for a total of a mean of 6.6 therapeutic cycles (3 to 10). Left ventricular ejection fraction (LVEF) determined by radionuclide ventriculography and circulating ANF were measured periodically in all patients. Epidx administration was limited at a cumulative dose ranging between 840 and 1200 mg/m2 because of a 25% decrease in LVEF and due to a progressive rising in ANF plasma levels. Furthermore, two patients who presented clinical symptoms of CHF had also significantly increased ANF levels (56 and 49% respectively). The current evidence suggests an important pathophysiological role of ANF in anthracyclinic related CHF. Hopefully measurement of plasma ANF will provide a simple non-invasive method of assessing ventricular dysfunction related to anthracycline cardiac toxicity and might represent an additional objective indicator of the severity of haemodynamic compromise in patients with impaired cardiac function.

Topics: Adult; Aged; Atrial Natriuretic Factor; Breast Neoplasms; Cardiomyopathies; Dose-Response Relationship, Drug; Epirubicin; Female; Humans; Middle Aged; Stroke Volume

Breast cancer is one of the most common cancers worldwide among women, and angiogenesis has an important effect on its growth and metastasis. Glipizide, which is a widely used drug for type 2 diabetes mellitus, has been reported to inhibit tumor growth and metastasis by upregulating the expression of natriuretic peptide receptor A (NPRA). Atrial natriuretic peptide (ANP), the receptor of NPRA, plays an important role in angiogenesis. The purpose of this study was to explore the effect of glipizide combined with ANP on breast cancer growth and metastasis.. This study aimed at investigating the effect of glipizide combined with ANP on breast cancer. Glipizide, ANP, or glipizide combined with ANP was intraperitoneally injected into MMTV-PyMT mice. To explore whether the anticancer efficacy of glipizide combined with ANP was correlated with angiogenesis, a tube formation assay was performed.. Glipizide combined with ANP was found to inhibit breast cancer growth and metastasis in MMTV-PyMT mice, which spontaneously develop breast cancer. Furthermore, the inhibitory effect of ANP combined with glipizide was better than that of glipizide alone. ANP combined with glipizide significantly inhibited tube formation of human umbilical vein endothelial cells (HUVECs) by suppressing vascular endothelial growth factor (VEGF)/VEGFR2 (vascular endothelial growth factor receptor 2) signaling.. These results demonstrate that glipizide combined with ANP has a greater potential than glipizide alone to be repurposed as an effective agent for the treatment of breast cancer by targeting tumor-induced angiogenesis.

Topics: Angiogenesis Inhibitors; Animals; Atrial Natriuretic Factor; Breast Neoplasms; Cell Movement; Cell Proliferation; Diabetes Mellitus, Type 2; Female; Glipizide; Human Umbilical Vein Endothelial Cells; Humans; Mice; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

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Topics: Animals; Atrial Natriuretic Factor; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Computational Biology; Extracellular Matrix; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Kruppel-Like Transcription Factors; MCF-7 Cells; Mice, Nude; Promoter Regions, Genetic; Protein Binding; Transplantation, Heterologous; Tumor Burden

Anthracycline-containing chemotherapy can cause irreversible and progressive left ventricular dysfunction. Epirubicin, which is widely used for breast cancer chemotherapy, is an anthracycline that has less cardiac toxicity than doxorubicin. The present report describes the case of a 70-year-old woman with breast cancer who developed severe congestive heart failure and severe cardiac dysfunction at 6 weeks from epirubicin final administration. Left ventricular function gradually improved after intensive treatment for heart failure and recovered completely within 2 months. To the best of our knowledge, this is the first report to describe epirubicin-induced subacute reversible cardiotoxicity.

Topics: Aged; Antibiotics, Antineoplastic; Atrial Natriuretic Factor; Breast Neoplasms; Cardiomyopathies; Cardiotonic Agents; Diuretics; Dobutamine; Echocardiography; Electrocardiography; Epirubicin; Female; Heart Failure; Heart Ventricles; Humans; Magnetic Resonance Imaging, Cine; Respiration, Artificial; Severity of Illness Index; Treatment Outcome

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

Circulating apoptotic proteins are increased in patients with heart failure. We evaluated whether circulating soluble (s) apoptosis-related proteins and inflammation markers are increased in long-term disease free breast cancer survivors and associated with cardiotoxicity, and if subgroups could be identified based on the applied treatments. Circulating tumour necrosis factor (TNF) alpha, sTNF-receptor (sTNF-R) 1 and 2, sFas, sFas ligand, sTNF-related apoptosis inducing ligand (sTRAIL) and serum HER2 were measured with immunoassay. High-sensitivity C-reactive protein (HS-CRP), fibrinogen, plasma B-type and N-terminal atrial natriuretic peptide (NT-ANP and BNP) were also determined. Thirty-four patients with median 6.0 years follow-up and 12 healthy age-matched women were enrolled. Chemotherapy, consisting of five cycles fluorouracil, epirubicin (90 mg/m(2)), cyclophosphamide (FEC) (n=14) or four cycles FEC followed by myeloablation with high-dose carboplatin, cyclophosphamide, thiotepa (n=20), preceded irradiation and tamoxifen. Circulating apoptosis markers were higher in patients than in controls. No associations with cardiac dysfunction were observed. sFas ligand and sTRAIL were higher in the high-dose than in the standard-dose group. In conclusion, we observed increased circulating apoptotic protein levels in long-term disease-free breast cancer survivors, treated with adjuvant chemoradiotherapy, particularly after myeloablative chemotherapy. The potential relation with late cardiotoxicity of antineoplastic therapy deserves further study.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Atrial Natriuretic Factor; Breast Neoplasms; C-Reactive Protein; Cross-Sectional Studies; Disease-Free Survival; fas Receptor; Female; Heart Failure; Humans; Membrane Glycoproteins; Middle Aged; Myocardium; Natriuretic Peptide, Brain; Radiotherapy; Receptor, ErbB-2; Tamoxifen; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha

A family of six hormones, i.e. atrial natriuretic peptide, brain natriuretic peptide, C-natriuretic peptide, long-acting natriuretic peptide, vessel dilator, and kaliuretic peptide's main known biologic properties are sodium and water excreting and blood pressure lowering.. These six hormones, each at their 1-microm concentrations, were evaluated for their ability to decrease the number and/or proliferation of breast adenocarcinoma cells in culture for 24, 48, 72, and 96 h.. Within 24 h, vessel dilator, long-acting natriuretic peptide, kaliuretic peptide, atrial natriuretic peptide and 8-bromo-cyclic GMP, a cell-permeable analogue of their intracellular mediator cyclic GMP (each at 1 microm), decreased the number of breast adenocarcinoma cells 60%, 31%, 27%, 40%, and 31%, respectively. There was no proliferation in the 3 days following this decrease in breast adenocarcinoma cell number. These same hormones decreased DNA synthesis 69% to 85% (P < 0.001). Brain natriuretic peptide and CNP did not decrease the number of breast adenocarcinoma cells or inhibit their DNA synthesis. Vessel dilator, long-acting natriuretic peptide, kaliuretic peptide and 8-bromo-cyclic GMP (each at 1 microM) decreased the number of cells in the S phase of the cell cycle by 62%, 33%, 50%, and 39%, respectively (all P < 0.05). Natriuretic peptide receptors-A and -C were present in the breast adenocarcinoma cells.. Four peptide hormones significantly decrease the number of human breast adenocarcinoma cells within 24 h and inhibit the proliferation of these cells for at least 96 h. Their mechanism of doing so involves inhibition of DNA synthesis and a decrease in cells in the S phase of the cell cycle mediated in part by cyclic GMP.

Topics: Adenocarcinoma; Atrial Natriuretic Factor; Blotting, Western; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclic AMP; DNA; Female; Guanylate Cyclase; Hormones; Humans; Middle Aged; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Peptide Fragments; Protein Precursors; Receptors, Atrial Natriuretic Factor

Topics: Aromatase Inhibitors; Arthroscopy; Atrial Natriuretic Factor; Breast Neoplasms; Estrogen Replacement Therapy; Exercise; Food Labeling; Health Care Costs; Heart Failure; Homocysteine; Humans; Knee Joint; Mosquito Control; Natriuretic Peptide, Brain; Peer Review, Research; Stents

To investigate whether plasma concentrations of atrial natriuretic peptide (ANP) could be used to identify patients with radiation mediated cardiac dysfunction.. Circulating levels of ANP were measured in patients who have been irradiated on a large part of the heart (50-80%; Hodgkin's disease) or smaller part of the heart (20-30%; primary breast cancer). C-terminal ANP was determined by radioimmunoassay (RIA) using a commercial kit.. In this study ANP plasma levels of 121 patients (Hodgkin's disease, 73 patients; breast cancer, 48 patients) and 67 controls were examined. ANP plasma levels of both Hodgkin patients (28.8+/-2.2, P=0.003) and breast cancer patients (20.4+/-2.8 ng/l, P=0.01) were significantly elevated when compared to age-matched controls (13.5+/-1.2 ng/l). Both for the Hodgkin (R=0.42, P=0.05) and breast cancer group (R=0.50, P=0.09) a positive relation between ANP plasma values and age was found. However, no clear relation between ANP plasma levels and time post treatment could be demonstrated. Patients with clinical symptoms of cardiovascular disease (n=25) had significantly higher ANP plasma levels (P<0.001) compared to patients in the same treatment group without evidence of cardiac disease (50.2+/-7.5 vs. 23.3+/-1.3 ng/l, P<0.001, and 38.2+/-12.4 vs. 16.3+/-1.6 ng/l, P<0.001, for Hodgkin's disease and breast cancer, respectively). Eight patients suffered from essential hypertension (n=8), whereas the remaining group of 17 patients showed a variety of cardiac disorders (i.e. myocardial infarction, decreasing ventricular function, and atrial fibrillations). In 11 patients cardiac problems were manifest either before or within a few years after mediastinal therapy. In two patients treated for Hodgkin's disease, and in four patients treated for breast cancer cardiac problems became manifest a long time (>10 years) after radiotherapy. Probably in this group of patients cardiac problems are related to the therapy.. The present study indicates that ANP plasma levels could be used to identify patients with radiation induced cardiac dysfunction.

Topics: Adult; Atrial Natriuretic Factor; Biomarkers; Breast Neoplasms; Cardiovascular Diseases; Female; Follow-Up Studies; Heart; Heart Diseases; Hodgkin Disease; Humans; Male; Mediastinum; Middle Aged; Radiation Injuries

To evaluate prospectively the cardiotoxic effects of epirubicin-containing adjuvant chemotherapy in breast cancer patients.. Patients (median age, 46 years; range, 28 to 55 years) were treated with five cycles of fluorouracil, epirubicin (90 mg/m2), and cyclophosphamide (FEC) (group I, n = 21) or with four cycles of FEC followed by high-dose chemotherapy consisting of cyclophosphamide, thiotepa, and carboplatin (group II, n = 19). Locoregional radiotherapy was applied subsequently. Cardiac evaluation was performed before chemotherapy (T0), 1 month after chemotherapy, 1 month after radiotherapy (T2), and 1 year after start of chemotherapy (T3). Left ventricular ejection fraction (LVEF) was determined by radionuclide ventriculography and diastolic function by echocardiography. Autonomic function was assessed by 24-hour ECG registration for heart rate variability (HRV) analysis. Time-corrected QT (QTc) was assessed and N-terminal atrial natriuretic peptide (NT-ANP) and brain natriuretic peptide (BNP) were measured as biochemical markers of cardiac dysfunction.. No patient developed overt congestive heart failure (CHF) and the mean LVEF declined from 0.61 at T0 to 0.54 at T3 (P =.001), resulting in an LVEF below 0.50 (range, 0.42 to 0.49) in 17% of the patients, whereas 28% had a decline of more than 0.10. Plasma NT-ANP levels increased gradually from 237 pmol/L at T0 to 347 pmol/L at T3 (P <.01), whereas plasma BNP levels increased from 2.9 pmol/L to 5.1 pmol/L (P =.04). Mean QTc increased from 406 msec at T0 to 423 msec at T3 (P <.01). No persistent alterations were found in diastolic function and HRV.. Relatively low doses of epirubicin in adjuvant chemotherapy for breast cancer results in mild subclinical myocardial damage demonstrated by a decline in LVEF, an increase in natriuretic peptide levels, and an increase in QTc, which may indicate a long-term risk of CHF.

Topics: Adult; Antibiotics, Antineoplastic; Atrial Natriuretic Factor; Breast Neoplasms; Cardiomyopathies; Chemotherapy, Adjuvant; Electrocardiography; Epirubicin; Female; Humans; Middle Aged; Prospective Studies; Ultrasonography; Ventriculography, First-Pass

By using N-terminal proatrial natriuretic peptide (proANP) in serum as a marker of cardiac function, we compared the cardiac side effects of two intensive adjuvant treatment regimens for breast cancer. Patients received either 9 cycles of FEC (5-fluorouracil, epirubicin and cyclophosphamide) where the doses of epirubicin and cyclophosphamide were escalated according to the leucocyte nadir (n = 49, FEC-group) or three cycles of FEC followed by high-dose chemotherapy with alkylating agents (n = 56, CTCb-group) given with the support of peripheral blood stem cells support. Both groups received adjuvant radiotherapy. Serial measurements of proANP were performed up to three years after treatment. Mean proANP values in the FEC-group was on average 19% higher than in the CTCb-group (p = 0.002). The proANP levels showed a significant association with the cumulative dose of epirubicin (p < 0.001) but not with cyclophosphamide (p = 0.151) and 5-FU (p = 0.160). The pharmacokinetics of epirubicin was studied at the first and third chemotherapy course. The proANP levels after treatment were significantly related to the AUC (p = 0.034) and Cmax(p = 0.037) of epirubicin. Left-sided chest irradiation was associated with on average 12% higher proANP values than right-sided (p = 0.031). We conclude that dose-escalated FEC causes a stronger increase in proANP than 3 FEC followed by high-dose CTCb-treatment. Increase of proANP levels might represent an early sign of cardiotoxicity secondary to chemotherapy and radiation treatment. Long-time follow-up is necessary to determine the clinical significance of these findings.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Atrial Natriuretic Factor; Biomarkers; Breast Neoplasms; Chemotherapy, Adjuvant; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Epirubicin; Female; Fluorouracil; Heart; Hematopoietic Stem Cell Transplantation; Humans; Middle Aged; Protein Precursors; Radiotherapy, Adjuvant; Risk Factors

Genomic actions of the hormone 1alpha,25-dihydroxy-vitamin D3(VD) are mediated by the transcription factor VDR, which is a member of the nuclear receptor superfamily. VDR acts in most cases as a heterodimeric complex with the retinoid X receptor (RXR) from specific DNA sequences in the promoter of VD target genes called VD response elements (VDREs). This study describes a mutation (K45A) of the VDR DNA binding domain that enhances the affinity and ligand responsiveness of VDR-RXR heterodimers on some VDREs. In analogy to a homologous mutation in the glucocorticoid receptor (K461A), this lysine residue appears to function as an allosteric 'lock'. Interestingly, overexpression of RXR was found to reduce the responsiveness and sensitivity of wild type VDR to VD, but enhance the response of VDRK45A. Moreover, the transactivation domains of both VDR and RXR were shown to be essential for obtaining responsiveness of the heterodimers to VD and 9- cis retinoic acid (the RXR ligand). This indicates that RXR is an active rather than silent partner of the VDR on the VDREs tested. Taken together, transactivation by VDR-RXR heterodimers can be triggered individually by all components of the protein-DNA complex, but full potency appears to be reached through allosteric interaction.

Topics: Alitretinoin; Allosteric Regulation; Animals; Atrial Natriuretic Factor; Breast Neoplasms; Calcitriol; COS Cells; Dimerization; DNA; Humans; Ligands; Point Mutation; Promoter Regions, Genetic; Rats; Receptors, Calcitriol; Receptors, Retinoic Acid; Recombinant Fusion Proteins; Retinoid X Receptors; Sequence Deletion; Transcription Factors; Transcriptional Activation; Tretinoin; Tumor Cells, Cultured

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Breast Neoplasms; Female; Humans; Lung Neoplasms; Male; Middle Aged; Pericardial Effusion; Pericardium; Punctures; Suction; Time Factors