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Atrial natriuretic peptide and long acting natriuretic peptide inhibit MEK 1/2 activation in human prostate cancer cells
Abstract
Atrial natriuretic peptide and long acting natriuretic peptide have anticancer effects in human prostate adenocarcinomas.
Atrial natriuretic peptide, long acting natriuretic peptide and cyclic GMP's effects on MEK 1/2 kinase were examined in human prostate adenocarcinoma cells.
Atrial natriuretic peptide and long acting natriuretic peptide decreased the activation of MEK 1/2 over a concentration range of 0.01 microM to 10 microM. Long acting natriuretic peptide and atrial natriuretic peptide (each 10 microM) inhibited the phosphorylation of MEK 1/2 kinase 97% (p < 0.00001) and 88% (p < 0.00001), respectively. The inhibition of MEK 1/2 was maximal at two hours, and ceased by four hours, secondary to both peptides. The ability of peptides to inhibit MEK 1/2 was inhibited by cyclic GMP antibody and cyclic GMP itself inhibited MEK 1/2 phosphorylation by 93%.
Atrial natriuretic peptide and long acting natriuretic peptide both inhibit MEK 1/2 kinase mediated via cyclic GMP as part of their anticancer mechanism(s) of action.
... A novel group of anticancer agents, i.e., peptides made by the human heart ( Figure 1) have at least a portion of their anticancer signaling via the Ras-MAPK pathway [7][8][9][10][11][12]. These peptides are termed atrial natriuretic peptides as they are synthesized mainly in the atrium rather than the ventricles of the heart in healthy animals and humans. ...
... ANP and LANP decreased the activation of MEK 1/2 over a concentration range of 0.01 µM to 10 µM [10]. LANP and ANP (each 10 µM) inhibited the phosphorylation of MEK 1/2 kinase by 97% (p < 0.00001) and 88% (p < 0.00001), respectively [10]. ...
... ANP and LANP decreased the activation of MEK 1/2 over a concentration range of 0.01 µM to 10 µM [10]. LANP and ANP (each 10 µM) inhibited the phosphorylation of MEK 1/2 kinase by 97% (p < 0.00001) and 88% (p < 0.00001), respectively [10]. The inhibition of MEK 1/2 was maximal at two hours and ceased by four hours secondary to both peptides [10]. ...
The heart is a sophisticated endocrine gland synthesizing the atrial natriuretic peptide prohormone which contains four peptide hormones, i.e., atrial natriuretic peptide, vessel dilator, kaliuretic peptide and long-acting natriuretic peptide, which decrease up to 97% of human pancreatic, breast, colon, prostate, kidney and ovarian carcinomas as well as small-cell and squamous cell lung cancer cells in cell culture. In vivo, these four cardiac hormones eliminate up to 80% of human pancreatic adenocarcinomas, two-thirds of human breast cancers, and up to 86% of human small-cell lung cancers growing in athymic mice. Their signaling in cancer cells includes inhibition of up to 95% of the basal activity of Ras, 98% inhibition of the phosphorylation of the MEK 1/2 kinases and 97% inhibition of the activation of basal activity of the ERK 1/2 kinases mediated via the intracellular messenger cyclic GMP. They also completely block the activity of mitogens such as epidermal growth factor's ability to stimulate ERK and Ras. They do not inhibit the activity of ERK in healthy cells such as human fibroblasts. The final step in their anticancer mechanism of action is that they enter the nucleus as demonstrated by immunocytochemical studies to inhibit DNA synthesis within cancer cells.
... The ability of the cardiac hormones to inhibit ERK 1/2 kinases [20,21] and to inhibit the mitogens that stimulate ERK 1/2 kinases [22] and the fact that ERK activates c-Fos [10] form part of the rationale for the present investigation to determine whether the cardiac hormones reduce c-Fos and c-Jun. Further rationale to investigate c-Fos is that the cardiac hormones are potent inhibitors of the other MAPK kinases in addition to ERK 1/2 kinases, that is, Ras and MEK 1/2 kinases [23][24][25][26] in the pathway that stimulate c-Fos [11]. Additional rationale to study the cardiac hormones is that they inhibit STAT-3 [27] and JNK [28], which activate c-Jun [13,14]. ...
... The present investigation suggests that they might directly inhibit c-Fos and c-Jun in cancer cells as nuclear extracts without cytoplasmic kinases present were utilized. The present findings are in addition to their ability to inhibit the Ras-MEK 1/2-ERK 1/2 kinase cascade [20][21][22][23][24][25][26], which enhances expression of c-Jun and c-Fos [10,11] (Fig. 1). There appears to be a complex interaction of the four cardiac hormones, c-Jun, c-Fos and MAP kinases within cancer cells, for in addition to the Ras-MEK 1/2-ERK 1/2 kinase cascade, another upstream regulator of c-Jun is JNK kinase(s), which phosphorylates c-Jun [13] and, in turn, JNK is inhibited (89%) by the four cardiac hormones [28] (Fig. 1). ...
... We hypothesize that the ability of the cardiac hormones to inhibit multiple steps that activate the proto-oncogenes and then inhibit the proto-oncogenes themselves in the nucleus as demonstrated in the present investigation is the reason why the cardiac hormones are able to eliminate up to 86% of human small-cell lung cancers [17] and up to 80% of human pancreatic cancers growing in mice [18] and why these cancers never recur in the lifespan of the mice once eliminated [17,18]. With respect to the mechanism(s) of how the cardiac hormones inhibit c-Fos and c-Jun, all of the cardiac hormones' effects within cancer cells are mediated via the intracellular messenger cyclic GMP [20][21][22][23][24][25][26][27]. Thus, utilizing an antibody to cyclic GMP blocks the effects of the cardiac hormones on ERK 1/2, MEK 1/2 and Ras [20][21][22][23][24][25][26][27]. ...
c-Fos is a cellular proto-oncogene which dimerizes with c-Jun proto-oncogene to form AP-1 transcription factor, which upregulates transcription of genes involved in proliferation and cancer formation. Four cardiac hormones, that is, long-acting natriuretic peptide (LANP), vessel dilator, kaliuretic peptide (KP) and atrial natriuretic peptide (ANP) with anticancer effects in vivo are potent inhibitors of the Ras-MEK 1/2-ERK 1/2 kinase cascade and signal transducer and activator of transcription-3 (STAT-3) that activate c-Fos and c-Jun. These four cardiac hormones were investigated for their effects on proto-oncogenes c-Fos and c-Jun within the nucleus of cancer cells.
Four cardiac hormones were evaluated for their ability to decrease proto-oncogenes c-Fos and c-Jun, measured by ELISA in extracted nuclei of three human cancer cell lines.
Vessel dilator, LANP, KP and ANP over a concentration range of 100 pM-10 μM, maximally decreased c-Fos by 61%, 60%, 61% and 59% in human hepatocellular cancer cells, by 82%, 74%, 78% and 74% in small-cell lung cancer cells, and by 82%, 73%, 78% and 74% in human renal adenocarcinoma cells. c-Jun was maximally reduced by vessel dilator, LANP, KP and ANP by 43%, 31%, 61% and 35% in hepatocellular cancer cells, by 65%, 49%, 59% and 40% in small-cell lung cancer cells, and by 47%, 43%, 57% and 49% in renal cancer cells.
Four cardiac hormones are potent inhibitors of c-Fos and c-Jun proto-oncogenes within the nucleus of cancer cells.
... When these four cardiac hormones synthesized by the ANP prohormone gene are given in concentrations higher than those synthesized by the heart, they have anticancer effects on human pancreatic cancers growing in athymic mice (Vesely et al. 2007a,c). BNP does not appear to have any anticancer effects (Gower et al. 2005, Vesely et al. 2005a,b, 2006c, 2007b. CNP has anticancer effects in vitro but only when given in 100-fold higher concentrations than the above four cardiac hormones synthesized by the ANP prohormone gene (Vesely et al. 2005b(Vesely et al. , 2006c. ...
... Cyclic GMP inhibits the activation of kinases in the Ras-MEK 1/2-ERK 1/2 kinase cascade that mediate the growth of cancers (Fig. 3). Thus, cyclic GMP blocks the conversion of inactive Ras-GDP to active Ras-GTP by 89% (Sun et al. 2009b), inhibits the phosphorylation of MEK 1/2 kinases by 93% (Sun et al. 2007b), and inhibits 83% of the phosphorylation of ERK 1/2 kinases (Sun et al. 2006b). ...
... Dose-response investigations indicate that BNP has no anticancer effects at any concentration (Gower et al. 2005, Vesely et al. 2005a,b, 2006c, 2007b. The addition of BNP for 24 h results in a 1, 2, and 4% (all nonsignificant) decrease in renal carcinoma cell numbers at its 1, 10, and 100 mM concentrations (Vesely et al. 2006c). ...
Four cardiac hormones namely, atrial natriuretic peptide, vessel dilator, kaliuretic peptide and long-acting natriuretic peptide, reduce up to 97% of all cancer cells in vitro. These four cardiac hormones eliminate up to 86% of human small-cell lung carcinomas, 2/3rds of human breast cancers, 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 kinase 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 the downstream targets of VEGF is Beta-catenin, which they reduce up to 88%. The WNT pathway is inhibited up to 68% and secreted Frizzled related protein 3 decreased up to 84% by the four cardiac hormones. AKT, a serine/threonine-protein kinase, is reduced up to 64% by the cardiac hormones. Signal transducer and activator of transcription 3 (STAT3), a final "switch" that activates gene expression that lead to malignancy, is decreased by up to 88% by the cardiac hormones. STAT3 is specifically decreased as they do not affect STAT1. There is cross-talk between the RAS-MEK 1/2-ERK 1/2 kinase cascade, VEGF, B-catenin, WNT, JNK and STAT pathways and each of these pathways is inhibited by the cardiac hormones.
... VEGF has its cancer growth-enhancing effects via stimulating Ras [6,7]-MEK1 ⁄ 2 [8,9]-ERK 1 ⁄ 2 [9][10][11] kinases while the cardiac hormones strongly inhibit (95-98% inhibition) the Ras-MEK 1 ⁄ 2-ERK 1 ⁄ 2 kinases [17][18][19][20][21][22]. The present investigation examined whether they may also inhibit an early step before this kinase cascade, that is VEGF itself or its VEGFR2 (KDR ⁄ Flk-1) receptor. ...
... The present investigation demonstrates that vessel dilator, long-acting natriuretic peptide (LANP), kaliuretic peptide and atrial natriuretic peptide (ANP) decrease the concentration of VEGF up to 64% in human small-cell lung, pancreatic and prostate cancer cells. This would appear to be an early effect in their anticancer multistep mechanism(s) of action because VEGF works within cancer cells via enhancing Ras-MEK 1 ⁄ 2-ERK 1 ⁄ 2 kinases' activity [6][7][8][9][10][11] and the four cardiac hormones inhibit the basal activity of each of these kinases 95% to 98% [17][18][19][20][21][22]. These kinases are downstream after VEGF binds to the VEGF-R2 (KDR ⁄ Flk-1) receptor, which is thought to be the active receptor mediating VEGF's effects on the growth of blood vessels into cancers, cancer growth itself and metastasis [1][2][3]13]. ...
... These kinases are downstream after VEGF binds to the VEGF-R2 (KDR ⁄ Flk-1) receptor, which is thought to be the active receptor mediating VEGF's effects on the growth of blood vessels into cancers, cancer growth itself and metastasis [1][2][3]13]. The ability of the cardiac hormones to decrease the amount of VEGF in cancer cells would appear to be an additional important mechanism of the cardiac hormones in eliminating cancer(s) in vivo [14][15][16] in addition to their ability [17][18][19][20][21][22] to inhibit the Ras-MEK 1 ⁄ 2-ERK 1 ⁄ 2 kinase cascade (i.e. multiple kinase inhibitors). ...
Background:
Vascular endothelial growth factor (VEGF) helps control tumour growth via causing new capillaries growth in tumours. Four cardiac hormones [i.e. vessel dilator, long-acting natriuretic peptide (LANP), kaliuretic peptide (KP) and atrial natriuretic peptide (ANP)] that eliminate up to up to 86% of human small-cell lung cancers growing in mice were investigated for their effects on VEGF and the VEGFR2/KDR/Flk-1 receptor. The VEGFR2 receptor is the main receptor mediating VEGF's cancer-enhancing effects.
Materials and methods:
Four cardiac hormones were evaluated for their ability to decrease VEGF/VEGFR2 measured by ELISAs in three human cancer cell lines.
Results:
Vessel dilator, LANP, KP and ANP, over a concentration range of 100 pM to 10 μM, maximally decreased the VEGFR2 receptor in human pancreatic adenocarcinoma cells by 48%, 49%, 74% and 83%. Vessel dilator, LANP, KP and ANP decreased the VEGFR2 receptor by 77%, 89%, 88% and 67% in human small-cell lung cancer cells and by 48%, 92%, 64% and 71% in human prostate cancer cells. These results were confirmed with the cardiac hormones also decreasing the VEGFR2 receptor measured by Western blots. VEGF itself in pancreatic carcinoma cells was decreased by 42%, 58%, 36% and 40% by vessel dilator, LANP, KP and ANP. VEGF levels were decreased 25%, 23%, 17% and 23% in small-cell lung cancer cells and decreased by 24%, 20%, 23% and 24% in prostate cancer cells by vessel dilator, LANP, KP and ANP.
Conclusion:
Four cardiac hormones are the first dual inhibitors of VEGF and the VEGFR2/KDR/Flk-1 receptor.
... decrease of JNK2 in human small cell lung cancer cells suggests that JNK2 is a molecular target of the cardiac hormones in cancer cells. The ability of the cardiac hormones to reduce the concentration of JNK2 in cancer cells would appear to be an additional important means of their eliminating carcinomas in vivo (13)(14)(15), in addition to their ability (18)(19)(20)(21)(22)(23) to inhibit the RAS-MEK 1/2-ERK 1/2 kinase cascade (i.e. multiple kinase inhibition). ...
... The four cardiac hormones inhibit each step in the RAS-MEK1/2-ERK 1/2 cascade (18)(19)(20)(21)(22)(23). Thus, they inhibit up to 95% of Ras (18,19), 98% of MEK 1/2 kinases (20,21), and 96% of ERK 1/2 kinases (22,23). ...
... The four cardiac hormones inhibit each step in the RAS-MEK1/2-ERK 1/2 cascade (18)(19)(20)(21)(22)(23). Thus, they inhibit up to 95% of Ras (18,19), 98% of MEK 1/2 kinases (20,21), and 96% of ERK 1/2 kinases (22,23). The present investigation demonstrates that they also inhibit another mitogen-activated protein kinase, i.e. ...
Four cardiac peptide hormones, namely vessel dilator, long-acting natriuretic peptide (LANP), kaliuretic peptide, and atrial natriuretic peptide (ANP) have anticancer effects.
The effects of these four cardiac hormones on human c-Jun-N-terminal kinase 2 (JNK2) were examined in human small cell lung cancer and human prostate cancer cells.
Vessel dilator, LANP, kaliuretic peptide and ANP maximally reduced expression of JNK2 by 89%, 56%, 45%, and 28%, respectively (each at p<0.0001) in human small cell lung cancer cells. In human prostate adenocarcinoma cells, JNK2 was maximally decreased 76%, 56%, 45%, (each at p<0.0001), and 28% (p<0.01) secondary to vessel dilator, LANP, kaliuretic peptide and ANP, respectively.
These results indicate that four cardiac hormones are significant inhibitors (by up to 89%) of JNK2 in human small cell lung cancer cells and up to 76% in human prostate adenocarcinoma cells as part of their anticancer mechanism(s) of action.
... This could be accomplished through the inhibition of protein kinases, such as those present in T-47D breast cancer cells, which control growth promoting signals. 20,21 The possible mechanism of ANP as an anticancer agent may be driven by the intracellular messenger system, cyclic guanosine monophosphate (GMP), formed by the activation of enzyme guanylate cyclase. The natriuretic peptide receptor-A (NPR-A) contains a catalytic portion of guanylate cyclase. ...
... These findings suggest that ANP's antiproliferative abilities may be induced by its inhibition of various protein kinase growth-promoting signals. 20,21 These results may illustrate ANP's therapeutic potential as an anticancer compound. 22 ...
The atrial natriuretic peptide (ANP) hormone is secreted by cardiac atrial myocytes and acts to regulate blood pressure homeostasis in humans. Previous research indicates ANP treatment significantly decreases the proliferation of human prostate cancer cells, pancreatic adenocarcinoma, and breast cancer cells. Minimal studies have been conducted with regard to ANP regulating tumor suppressor genes and steroid hormone receptors in breast cancer cells. Our study analyzed the effects of ANP in combination with 17β-estradiol (E2) and antiestrogen treatments on p53 and ERα levels in T-47D breast cancer cells. Preliminary studies through Western blot analysis showed that ANP treatment decreases p53 and ERα expression levels in a concentration-dependent (10–100 nM) manner. Treatment with ANP alone, at a 100 nM concentration, causes a decrease of p53 and ERα expression compared with Cs (control stripped), but with E2 and antiestrogen combinations, expression of both protein levels decreased compared with treatments without ANP. Combined treatment with E2, an estrogen antagonist, and ANP decreased cellular proliferation compared with treatments without ANP, except in the case of raloxifene (RAL). Our studies indicate that ANP has potential as a therapeutic breast cancer treatment and should inspire further studies on the molecular mechanism of ANP in T-47D breast cancer cells.
... NPCR has the greatest affinity for the Atrial Natriuretic peptide (ANP) (81), which has been linked to controlling PCa progression (82), therefore an increase in NPCR expression may enhance PCa progression. One of the anticancer effects of long-lasting ANP is the inhibition of phosphorylation and activation of MEK1/2 and ERK1/2 via cyclic GMP activation (83,84), which is required for the activation of AR signalling. This mechanism is also immunomodulatory in the tumour microenvironment of PCa (85). ...
Persistent androgen receptor (AR) signalling is the main driver of prostate cancer (PCa). Truncated isoforms of the AR called androgen receptor variants (AR-Vs) lacking the ligand binding domain often emerge during treatment resistance against AR pathway inhibitors such as Enzalutamide. This review discusses how AR-Vs drive a more aggressive form of PCa through the regulation of some of their target genes involved in oncogenic pathways, enabling disease progression. There is a pressing need for the development of a new generation of AR inhibitors which can repress the activity of both the full-length AR and AR-Vs, for which the knowledge of differentially expressed target genes will allow evaluation of inhibition efficacy. This review provides a detailed account of the most common variant, AR-V7, the AR-V7 regulated genes which have been experimentally validated, endeavours to understand their relevance in aggressive AR-V driven PCa and discusses the utility of the downstream protein products as potential drug targets for PCa treatment.
... Sun et al. reported that ANP and LANP treatment could effectively inhibit the conversion of the RAS-GDP signal to the RAS-GTP signal in prostate cancer cells [88]. In addition, ANPs could suppress the activation of MEK1/2 and ERK1/2 in prostate cancer cells, and the inhibitory effect could be largely abolished by the cGMP antibody [89]. EGF and insulin were shown to stimulate ERK 1/2 kinases through mediating conversion of RAS-GDP to active RAS-GTP [90]. ...
The atrial natriuretic peptide (ANP), a cardiovascular hormone, plays a pivotal role in the homeostatic control of blood pressure, electrolytes, and water balance and is approved to treat congestive heart failure. In addition, there is a growing realization that ANPs might be related to immune response and tumor growth. The anti-inflammatory and immune-modulatory effects of ANPs in the tissue microenvironment are mediated through autocrine or paracrine mechanisms, which further suppress tumorigenesis. In cancers, ANPs show anti-proliferative effects through several molecular pathways. Furthermore, ANPs attenuate the side effects of cancer therapy. Therefore, ANPs act on several hallmarks of cancer, such as inflammation, angiogenesis, sustained tumor growth, and metastasis. In this review, we summarized the contributions of ANPs in diverse aspects of the immune system and the molecular mechanisms underlying the anti-cancer effects of ANPs.
... Mutated in up to 30% of the human malignancies, RAS proteins are the main members of the superfamily of small GTP binding and hydrolyzing proteins (GTPases) which are mainly responsible for transducing extracellular proliferative signals modulated by receptor tyrosine kinases (RTKs) in response to different groups of growth factors, including epidermal growth factor. Furthermore, LANP is capable of inhibiting 80-90% of the MEK1/2 and ERK1/2 activities in the prostate cancer cells [37,38]. ...
Development of engineered non-pathogenic bacteria, capable of expressing anti-cancer proteins under tumor-specific conditions, is an ideal approach for selectively eradicating proliferating cancer cells. Herein, using an engineered hypoxia responding nirB promoter, we developed an engineered Escherichia coli BW25133 strain capable of expressing cardiac peptides and GFP signaling protein under hypoxic condition for spatiotemporal targeting of mice mammary tumors. Following determination of the in vitro cytotoxicity profile of the engineered bacteria, selective accumulation of bacteria in tumor microenvironment was studied 48 h after tail vein injection of 10⁸ cfu bacteria in animals. For in vivo evaluation of antitumoral activities, mice with establishment mammary tumors received 3 consecutive intravenous injections of transformed bacteria with 4-day intervals and alterations in expression of tumor growth, invasion and angiogenesis specific biomarkers (Ki-67, VEGFR, CD31and MMP9 respectively), as well as fold changes in concentration of proinflammatory cytokines were examined at the end of the 24-day study period. Intravenously injected bacteria could selectively accumulate in tumor site and temporally express GFP and cardiac peptides in response to hypoxia, enhancing survival rate of tumor bearing mice, suppressing tumor growth rate and expression of MMP-9, VEGFR2, CD31 and Ki67 biomarkers. Applied engineered bacteria could also significantly reduce concentrations of IL-1β, IL-6, GC-SF, IL-12 and TNF-α proinflammatory cytokines while increasing those of IL-10, IL-17A and INF-γ. Overall, administration of hypoxia-responding E. coli bacteria, carrying cardiac peptide expression construct could effectively suppress tumor growth, angiogenesis, invasion and metastasis and enhance overall survival of mice bearing mammary tumors.
... Reported by Sun et al., VD and KP demonstrate their anti-cancer activities in prostate cancer through inhibiting RAS activity (Sun et al., 2010). Furthermore, LANP is capable of inhibiting 80-90% of MEK1/2 and ERK1/2 activity in prostate cancer cells (Sun et al., 2006, Sun et al., 2007. As ERK plays an important role in controlling apoptosis, inhibition of its phosphorylation and activation by LANP may partly explain its pro-apoptotic mechanism of action (Vesely et al., 2005). ...
Background
Application of genetically modified non-pathogenic bacteria expressing specific anti-tumor proteins under certain conditions specific to tumors is an effective approach for selective targeting of tumors. We developed here, for the first time, a novel spatiotemporal cancer targeted therapy applying engineered E. coli bacteria with capability of expressing cardiac peptides under hypoxic conditions of tumor.
Method
E. coli BW25133 was transformed with construction of co-expressing cardiac hormones and GFP. Bacteria bearing constructs were then IV administered in mice bearing tumors and then tumor localization, as well as tumor proliferation, invasion and angiogenesis biomarkers (Ki-67, VEGFR, CD31and MMP9), changes in cytokine profile, suppression of tumor growth and survival were analyzed.
Results
IV Administered bacteria bearing constructs could specifically localize at tumor site and express cardiac peptides under hypoxic conditions. Administration of bacteria significantly enhanced survival rate, suppressed tumor progression and lowered expression levels of MMP-9, VEGFR2, CD31 and Ki67 as potent markers for angiogenesis, tumor proliferation and metastasis. Furthermore, applied bacteria resulted in significant reduction in the expression of IL-1β, IL-6, GC-SF, IL-12 and TNF-α proinflammatory cytokines, whereas increasing IL-10, IL-17A and INF-γ cytokines.
Conclusion
Overall, administration of E. coli bearing cardiac hormone expression construct could effectively suppress tumor growth, angiogenesis, invasion and metastasis while enhancing survival rate in mice model of breast cancer.
... Many studies have described the potency of ANP on inhibiting tumor growth both in vitro and in vivo [28]. Particularly, the anti-proliferative efficacy of ANP without inducing apoptosis [64] has been extensively demonstrated in various forms of human cancer, including pancreatic adenocarcinoma, breast, prostate, colon, renal, ovarian, small cell and squamous cell lung cancers, [65]. Therefore, ANP and other natriuretic peptides (i.e. ...
... Many studies have described the potency of ANP on inhibiting tumor growth both in vitro and in vivo [28]. Particularly, the anti-proliferative efficacy of ANP without inducing apoptosis [64] has been extensively demonstrated in various forms of human cancer, including pancreatic adenocarcinoma, breast, prostate, colon, renal, ovarian, small cell and squamous cell lung cancers, [65]. Therefore, ANP and other natriuretic peptides (i.e. ...
Through the recent development of knowledge in biotechnology and bioinformatics, snake venoms are widely used to develop new drugs to treat diseases such as hypertension and cancer. We have previously reported that Lebetin 2 isolated from Macrovipera lebetina transmediterranea venom displays a potent anti-platelet activity and exerts a cardioprotective effect in ischemia-reperfusion (IR) injury model. Here, we report that Lebetin 2 possess an anti-tumor effect by targeting the integrin receptor function. It was thus able to inhibit both adhesion and migration of pheochromocytoma cells (PC12) and α1β1 integrin-expressing CHO cells (CHO-α1) to type I and IV collagens. Moreover, this peptide affects proliferation of PC12 cells by modulating AKT phosphorylation. Furthermore, Lebetin 2 exhibits a potent anti-angiogenic effect as assessed in vitro and ex vivo, using both the embryo chick chorioallantoic membrane model (CAM) and rat aortic ring assay. Interestingly, the interaction mode of Lebetin 2 with the integrin α1β1, assessed in silico, showed that the peptide represents a steric obstruction preventing the collagen from enforcing the interactions with the integrin.
... Moreover, the vessel dilator and kaliuretic peptide exhibited anti-cancer properties against human prostate carcinoma by inhibiting Ras activity [120]. Sun et al. found that LANP and ANP significantly inhibited (80-90%) MEK1/2 and ERK1/2 activity in human prostate adenocarcinoma cells [121][122][123]. ...
Cancer along with cardiovascular disease are the main causes of death in the industrialised countries around the World. Conventional cancer treatments are losing their therapeutic uses due to drug resistance, lack of tumour selectivity and solubility and as such there is a need to develop new therapeutic agents. Therapeutic peptides are a promising and a novel approach to treat many diseases including cancer. They have several advantages over proteins or antibodies: as they are (a) easy to synthesise, (b) have a high target specificity and selectivity and (c) have low toxicity. Therapeutic peptides do have some significant drawbacks related to their stability and short half-life. In this review, strategies used to overcome peptide limitations and to enhance their therapeutic effect will be compared. The use of short cell permeable peptides that interfere and inhibit protein-protein interactions will also be evaluated.
... The next step (Figure 1) in the RAS-MEK1/2-ERK1/2 kinase cascade involves two kinases, MEK1 and MEK2 (46,47). Vessel dilator, LANP, kaliuretic peptide and ANP inhibit the phosphorylation of MEK1/2 kinases by 98%, 97%, 81% and 88%, respectively (48,49). ERK1/2 are important targets for inhibiting the growth of cancer (50,51). ...
Conclusion:
These multiple kinase inhibitors have both adjunct and primary anticancer effects.
... The antitumor activity of ANP has been mainly related to its interaction with the specific receptors NPRs [3][4][5][6][7][8][9]20], through which this natriuretic hormone inhibits some meta-bolic targets crucial for cancer development, including the GTPase RAS [21,60,61], the MEK1/2 kinases [22,62] and ERK 1/2 kinases [23] (Fig. 5 and Table 1). Mitogen stimulation of RAS and ERK 1/2 as well as the VEGF receptor signaling are also inhibited by ANP [21,24,61,63]. ...
Atrial natriuretic peptide (ANP) is a cardiac hormone playing a crucial role in cardiovascular homeostasis mainly through blood volume and pressure regulation. In the last years, the new property ascribed to ANP of inhibiting tumor growth both in vitro and in vivo has made this peptide an attractive candidate for anticancer therapy. The molecular mechanism underlying the anti-proliferative effect of ANP has been mainly related to its interaction with the specific receptors NPRs, through which this natriuretic hormone inhibits some metabolic targets critical for cancer development, including the Ras-MEK1⁄2-ERK1⁄2 kinase cascade, functioning as a multikinase inhibitor. In this review we summarize the current knowledge on this topic, focusing on our recent data demonstrating that the antitumor activity of this natriuretic hormone is also mediated by a concomitant effect on the Wnt/β-catenin pathway and on the pH regulation ability of cancer cells, through a Frizzled-related mechanism. This peculiarity of simultaneously targeting two processes crucial for neoplastic transformation and solid tumor survival reinforces the utility of ANP for the development of both preventive and therapeutic strategies.
... The significant (P \ 0.0001) decrease in STAT 3 in human small-cell lung cancer cells and in human pancreatic cancer cells suggests that STAT 3 is a molecular target of the cardiac hormones in cancer cells. Their ability to inhibit STAT 3 would appear to be an additional important mechanism of their eliminating human cancers in vivo [9][10][11] in addition to their ability to inhibit the Ras-MEK 1/2-ERK 1/2 kinase cascade (i.e., multiple kinase inhibitors [12,13,[15][16][17][18]. ERK 1/2 kinases activate STAT 3 in response to growth factors [8]. ...
Signal transducers and activators of transcription (STATs) are the final "switches" that activate gene expression patterns that lead to human malignancy. Extracellular signal-regulated kinases (ERK 1/2) activate STAT 3; four cardiovascular hormones inhibit ERK 1/2 kinases, leading to the hypothesis that they may also inhibit STATs. These four cardiac hormones, i.e., vessel dilator, long-acting natriuretic peptide (LANP), kaliuretic peptide, and atrial natriuretic peptide (ANP), eliminate human cancers growing in mice. These four cardiac hormones' effects on STATs 1 and 3 were examined in human small-cell lung cancer and human pancreatic adenocarcinoma cells. Vessel dilator, LANP, kaliuretic peptide, and ANP maximally decreased STAT 3 by 88, 54, 55, and 65 %, respectively, at their 1 μM concentrations in human small-cell lung cancer cells and STAT 3 by 66, 57, 70, and 77 % in human pancreatic adenocarcinoma cells, respectively. The cardiac hormones (except LANP) also significantly decreased STAT 3 measured by Western blots. These cardiac hormones did not decrease STAT 1 in either human small-cell lung cancer or pancreatic adenocarcinoma cells. We conclude that these four cardiac hormones are significant inhibitors of STAT 3, but not STAT 1, in human small-cell lung cancer and pancreatic adenocarcinoma cells, which suggests a specificity for these hormones' anticancer mechanism(s) of action enzymology in human cancer cells.
Background
Colorectal cancer (CRC) is a common malignant disease that involves the interaction of both genetic and environmental factors. Trametinib (TNB) has been approved alone or in combination with dabrafenib to treat melanoma. Vessel dilator (VDL) is a cardiac hormone that possesses anticancer properties. This study evaluates TNB with VDL combined effects in CRC cells and explores the role of Mutagen-activated protein kinases (MAPK, ERK1/2) in this effect.
Methods
The HCT-15 CRC cells were treated with TNB and VDL. The MTT and ELISA assays were used to assess p-ERK, VEGF, and VEGFR levels.
Results
The results showed that combined treatment of TNB with VDL produced a significant and synergistic inhibition of HCT-15 cell growth with a combination index of less than 1. A combination treatment demonstrated no change in the expression of VEGF, inhibition of VEGFR2, and reduction of p-ERK1/2 in HCT-15 cells.
Conclusion
The findings encourage further evaluation of this combination as the combined effect is not mediated through p-ERK, VEGF, and VEGFR.
Medicines derived from proteins thrive in the clinic, thanks to a surge in public awareness of their potential. Therapeutic proteins are classified into five types based on their pharmacological perspective. (a) substituting a defective or uncommon protein; (b) enhancing an accessible route; (c) offering a unique utility or action; (d) acting together with a molecule or organism; and (e) distributing other substances effectors proteins, namely radionuclides and cytotoxic medications. The therapeutic proteins of molecular categories include antibodies, Fc fusion proteins, anticoagulants, blood factors, bone morphogenetic proteins, engineered protein scaffolds, enzymes, growth factors, hormones, interferons, interleukins, and thrombolytic proteins. They can also be divided into three categories based on their molecular mode of action: (a) non-covalently attaching to targets, like mAbs; (b) modifying covalent bonds, like enzymes; and (c) exerting activity without particular contacts, like serum albumin. Several recombinant medications were used in the therapeutic protein approaches and are under clinical trials for various chronic diseases and disorders because of their effectiveness against diseases. Pharmaceutical companies rely more and more on protein-based research to develop new and effective treatments. Various investigation reports exhibited that there has been considerable advancement in the synthesis and application of therapeutic proteins in recent years. Even though protein-based medicines have taken centre stage in pharmacological research and have improved human safety, numerous glitches exist regarding safety and immunogenicity, stability of protein, and degradation concern. Nanoparticles are being used in a growing number of applications, including therapeutic and diagnostic chemical delivery. Biocompatibility and biodegradability are two advantages of protein nanoparticles in general. Due to their well-defined core structure, protein-based nanoparticles also allow for various surface alterations, such as covalent drug attachment and targeting ligands. This chapter discusses the most notable advances in therapeutic proteins and protein nanoparticle technology and its applications in drug administration and protein nanoparticles employed in cancer treatment.KeywordsTherapeutic proteinsProteinsProtein nanomaterialsDrug targetingTherapeuticsPolypeptides
Peptides have emerged as powerful platform technologies to engineer effective therapies against cancer. Peptides play significant role as clinically important molecules in developing next-generation cancer therapeutics by targeting signalling pathways, cell cycle, tumour suppressor protein, transcription factor, ion channels, several G-protein-coupled receptors and matrix metalloproteinases MMP 2 and MMP 9. Peptide-based cancer vaccines also hold huge promise in cancer treatment. Peptide-based biomarkers have immense potential to facilitate the early detection of cancer and thus increase the lifespan of cancer patients. Additionally, peptides also act as safe clinically suitable molecular medicine transporters for cancer treatment. Cell-penetrating cationic peptides, lipopeptides, amphipathic peptides and mini-proteins facilitate nucleic acid-based drug delivery and can be exploited for developing siRNA-based nanotherapeutics and combination therapy against cancer. Peptide-based medicines and molecular transporters play significant role in managing adaptive chemotherapeutic drug resistance and metastasis against cancer. Here we have discussed the current status and emerging opportunities of peptides as molecular medicines and molecular transporters.
The Wnt signaling pathway is a signal transduction pathway associated with oncogenesis in several human cancers. 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. These cardiac hormones were evaluated for their ability to inhibit Wnt-3a with a solid phase ELISA in human colorectal cancer cells, pancreatic carcinoma cells, and renal adenocarcinoma cells. In human pancreatic carcinoma cells, Wnt-3a was maximally decreased 66%, 66%, 68%, and 67% (each at p<0.0001) secondary to vessel dilator, kaliuretic peptide, ANP and LANP. Vessel dilator, kaliuretic peptide, ANP, and LANP maximally reduced the concentration of Wnt-3a by 53%, 52%, 53%, and 51% respectively (each at p<0.0001) in human colorectal adenocarcinoma cells. In human renal adenocarcinoma cells, Wnt-3a was maximally inhibited by vessel dilator, kaliuretic peptide, ANP, and LANP by 43%, 43%, 44%, and 42% (each at p<0.0001), respectively. This study indicates that four cardiac hormones are significant inhibitors (up to 68%) of Wnt-3a in human cancer cells as part of their anticancer mechanism(s) of action.
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.
Four cardiac hormones are synthesized by the atrial natriuretic peptide prohormone gene. These hormones, namely, long-acting natriuretic peptide, vessel dilator, kaliuretic peptide, and atrial natriuretic peptide, help regulate blood pressure and blood volume by causing vasodilation, diuresis, and sodium excretion. These cardiac hormones reduce up to 97% of all cancer cells in vitro. These cardiac hormones eliminate up to 86% of human small-cell lung carcinomas, two thirds of human breast cancers, 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 diphosphate conversion to RAS guanosine triphosphate (95% inhibition)-mitogen-activated protein kinase kinase 1/2 (98% inhibition)-extracellular signal-related kinase 1/2 (96% inhibition) cascade in cancer cells. They also reduce c-Jun-N-terminal kinase 2 up to 89%. These multiple kinase inhibitors are also inhibitors of vascular endothelial growth factor (VEGF) and its VEGFR2 receptor (up to 89% inhibition). They reduce β-catenin up to 88%. They inhibit the WNT pathway up to 68%, and secreted Frizzled-related protein 3 is decreased up to 84%. AKT, a serine/threonine-protein kinase, is reduced up to 64% by the cardiac hormones. Signal transducer and activator of transcription 3, a final "switch" that activates gene expression that leads to malignancy, is decreased by up to 88% by the cardiac hormones. Of importance, the cross talk between the multiple kinases, VEGF, B-catenin, WNT, and STAT pathways is inhibited by the 4 cardiac hormones.
Atrial natriuretic peptide has been recently discovered to have anticancer effects via interaction with cell surface natriuretic peptide receptor A (NPRA) and natriuretic peptide clearance receptor (NPRC). In a preclinical model, NPRA expression has been identified during the tumor angiogenesis and may serve as a potential prognostic marker and target for prostate cancer (PCa) therapy. However, the presence of NPRC receptor in PCa model has not yet been assessed. Furthermore, there is still no report using nanoparticle for PCa position emission tomography (PET) imaging. Herein, an amphiphilic comb-like nanoparticle was synthesized with controlled properties through modular construction containing C-atrial natriuretic factor (CANF) for NPRC receptor targeting and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator for high specific activity Cu-64 radiolabeling. The pharmacokinetics of 64Cu-CANF-Comb exhibited tuned biodistribution and optimized in vivo profile in contrast to the non-targeted 64Cu-Comb nanoparticle. PET imaging with 64Cu-CANF-Comb in CWR22 PCa tumor model showed high blood pool retention, low renal clearance, enhanced tumor uptake, and decreased hepatic burden relative to the non-targeted 64Cu-Comb. Immunohistochemistry staining confirmed the presence of NPRC receptor in tumor tissue. Competitive PET receptor blocking study demonstrated the targeting specificity of 64Cu-CANF-Comb to NPRC receptor in vivo. These results establish a new nanoagent for prostate cancer PET imaging.
The heart is a sophisticated endocrine gland synthesizing the atrial natriuretic peptide (ANP) prohormone which contains four peptide hormones, namely atrial natriuretic peptide, vessel dilator, kaliuretic peptide and long-acting natriuretic peptide, which decrease up to 97% of human pancreatic, breast, colon, prostate, kidney and ovarian carcinomas, as well as small-cell and squamous cell lung cancer cells within 24 hours in cell culture. In vivo these four cardiac hormones eliminate up to 80% of human pancreatic adenocarcinomas, up to two-thirds of human breast cancers, and up to 86% of human small-cell lung cancers in athymic mice. Their anticancer mechanism(s) target the Rat sarcoma bound guanosine triphosphate (RAS)-mitogen activated protein kinase kinase 1/2 (MEK1/2)-extracellular signal related kinase 1/2 (ERK1/2) kinase cascade in cancer cells. These four cardiac hormones inhibit up to 95% of the basal activity of Ras, 98% of the phosphorylation of MEK1/2 kinases and 96% of the activation of basal activity of ERK1/2 kinases. They also completely block the activity of mitogens such as the ability of epidermal growth factor to stimulate ERK and RAS. In addition to inhibiting these mitogen-activated protein kinases (MAPKs) they also inhibit MAPK9, i.e. c-Jun-N-terminal kinase 2. These multiple kinase inhibitors are cytotoxic and cause cell death of cancer cells but not of normal cells.
Four cardiac hormones, namely, vessel dilator, long-acting natriuretic peptide, atrial natriuretic peptide and kaliuretic peptide, have anticancer effects but whether they cause cell death of human cancer cells or normal cells is unknown.
These cardiac hormones were examined for their ability to cause cell death quantified by measurement of nuclear matrix proteins 41/7 which is a function of the number of dead or dying cells.
Each of these cardiac hormones caused cell death in up to 36% (p < 0.0001) of the pancreatic adenocarcinoma cells and up to 28% (p<0.0001) of the prostate cancer cells over a concentration range of 100 pmol/l to 10 μmol/l. There was no cell death of normal human prostate, kidney, or lung cells at the above concentrations.
Four cardiac hormones cause death of pancreatic and prostate cancer cells but not of normal prostate, lung, or kidney cells.
Four cardiac hormones, i.e. atrial natriuretic peptide (ANP), vessel dilator, long-acting natriuretic peptide (LANP) and kaliuretic peptide (KP), have anticancer effects both in vitro and in vivo. The sustained decrease in number of human pancreatic adenocarcinoma cells for 3 days secondary to the four hormones noted previously suggests a decrease in proliferation of pancreatic cancer cells not eliminated after initial treatment.
Four cardiac hormones were evaluated for their ability to directly decrease proliferation of human pancreatic cancer cells with comparison of their effects on proliferation on normal human lung, kidney, prostate and endothelial cells.
ANP, LANP, vessel dilator and KP decreased the proliferation of viable human pancreatic adenocarcinoma cells by 39%, 73%, 26% and 32% respectively at their 0.01 microM concentrations compared with the proliferation of untreated pancreatic cancer cells. Maximal inhibition of proliferation (81%) occurred with LANP at its 0.1 microM concentration in dose-response studies. At these same concentrations, there was no decrease in proliferation of human kidney, lung, prostate or endothelial cells compared with untreated kidney, lung, prostate or endothelial cells.
Four cardiac hormones have strong anti-proliferative effects on human pancreatic adenocarcinoma cells while sparing human kidney, lung, prostate and endothelial cells from a similar strong anti-proliferative effect. This anti-proliferative effect on pancreatic cancer cells helps to explain why human pancreatic cancers in vivo treated with the cardiac hormones decrease to less than 10% of the volume of untreated pancreatic cancers as they proliferate less.
Four cardiac hormones synthesized by the same gene, i.e. atrial natriuretic peptide, vessel dilator, long acting natriuretic peptide and kaliuretic peptide, have anticancer effects in vitro.
These cardiac hormones were infused subcutaneously for 28 days with weekly fresh hormones at 0.3 nM kg(-1) body weight in athymic mice bearing human squamous cell carcinomas.
Vessel dilator, atrial natriuretic peptide and kaliuretic peptide each eliminated one in six (17%) of the human squamous cell lung carcinomas. Long-acting natriuretic peptide, although it did not eliminate any of the human squamous cell lung carcinomas did decrease the volume of one carcinoma to only 2% (P < 0.0001) of the untreated carcinomas. The squamous cell lung carcinomas that were not eliminated, with the exception of the one LANP-treated tumour that decreased to only 2% of the volume of the untreated cancers, grew rapidly but their growth velocity compared to controls decreased by 76%, 40%, 38% and 25% in the vessel dilator, atrial natriuretic peptide, kaliuretic peptide and long-acting natriuretic peptide groups respectively (P < 0.05).
Three of four cardiac hormones synthesized by the atrial natriuretic peptide gene can eliminate human squamous cell lung carcinomas in athymic mice when treated subcutaneously for 4 weeks. The 4th cardiac hormone, i.e. long-acting natriuretic peptide, decreased the volume of one squamous cell lung carcinoma to 2% of that of untreated animals, suggesting that it, too, has beneficial effects on squamous cell lung cancers.
Atrial natriuretic peptide (ANP) and vessel dilator eliminate 80% and 33% of human pancreatic adenocarcinomas growing in athymic mice when given subcutaneously for 28 days via osmotic pumps.
To determine if similar beneficial effects can be obtained by ANP and vessel dilator on a bi-weekly basis, bolus infusion via vascular ports bi-weekly for 4 weeks was given to athymic mice bearing human pancreatic adenocarcinomas.
Vessel dilator and ANP (each at 100 microM) (n=6 for each) resulted in a 33% (p<0.01) and 17% (p<0.05) elimination of human pancreatic adenocarcinomas, respectively, while the tumor volume increased 64-fold (p<0.001) in the placebo-treated mice (n=12). During the 4 weeks of treatment, the growth velocity decreased 92% and 68% with vessel dilator and ANP, respectively, compared to untreated mice.
Biweekly vessel dilator and ANP both eliminate some human pancreatic adenocarcinomas in athymic mice.
Four cardiac hormones synthesized by the same gene, i.e. atrial natriuretic peptide, vessel dilator, kaliuretic peptide and long-acting natriuretic peptide, have anticancer effects in vitro and in vivo. Epidermal growth factor's mechanism of cancer formation involves the activation of Ras.
These four cardiac hormones were evaluated for their ability to inhibit mitogen (epidermal growth factor) activation of Ras.
Epidermal growth factor increased the activation of Ras by 68%, 85% and 90% at its 1, 2 and 5 ng mL(-1) concentrations. Vessel dilator, long-acting natriuretic peptide, atrial natriuretic peptide and kaliuretic peptide inhibited 5 ng mL(-1) epidermal growth factor's stimulation of Ras by 73%, 79%, 33% and 45%, respectively, at their 1 microM concentrations. Their effects on epidermal growth factor's activation of Ras were specific with addition of the cardiac hormones' respective antibodies (5 microM) blocking 95%, 93%, 100% and 100% (P < 0.001 for each) of their ability to inhibit epidermal growth factor's stimulation of Ras.
Four cardiac hormones specifically inhibit epidermal growth factor's activation of Ras. This investigation would suggest that these cardiac hormones' anticancer effects involve the inhibition of mitogens such as epidermal growth factor's ability to activate Ras as well as inhibiting unstimulated basal activity of Ras.
The heart is a sophisticated endocrine gland synthesizing a family of peptide hormones by three different genes. These cardiac hormones are stored as 3 prohormones, i.e. atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) prohormones. Within the ANP prohormones are 4 peptide hormones, i.e. atrial natriuretic peptide, vessel dilator, kaliuretic peptide and long-acting natriuretic peptide (LANP) which decrease up to 97% of human pancreatic, breast, colon, prostate, kidney and ovarian carcinomas as well as small-cell and squamous cell lung cancer cells within 24 hours in cell culture. In vivo these 4 cardiac hormones eliminate up to 80% of human pancreatic adenocarcinomas, 2/3rds of human breast cancers, and up to 86% of human small-cell lung cancers in athymic mice. Their anticancer mechanism(s) target the Ras-MEK 1/2-ERK 1/2 kinase cascade in cancer cells. These 4 cardiac hormones inhibit up to 95% of the basal activity of Ras, 98% of the phosphorylation of MEK 1/2 and 97% of the activation of basal activity of ERK 1/2. They also completely block the activity of mitogens such as epidermal growth factor's ability to stimulate ERK. They do not inhibit the activity of ERK in healthy cells such as human fibroblasts. The final step in their anticancer mechanism of action is that they enter the nucleus as demonstrated by immunfluorescence to inhibit DNA synthesis within cancer cells.
Four cardiac hormones synthesized by the same gene, i.e. atrial natriuretic peptide, vessel dilator, long acting natriuretic peptide and kaliuretic peptide, and the kidney hormone urodilatin have anticancer effects in vitro.
These cardiac hormones and urodilatin were infused subcutaneously for 28 days with weekly fresh hormones since they lose biological effects at body temperature for more than a week at 0.3 nm kg(-1) body weight in athymic mice bearing human small-cell lung carcinomas.
Long acting natriuretic peptide, vessel dilator, kaliuretic peptide, atrial natriuretic peptide and urodilatin eliminated 86%, 71%, 57%, 43% (P < 0.001 for the cardiac hormones) and 25% (P < 0.05; urodilatin) of the human small-cell lung carcinomas. The treated small-cell lung carcinomas that were not cured grew rapidly, similar to the untreated controls, whose volume was 7 fold larger in 1 week, 18-fold increased in 2 weeks, 39-fold increased in 3 weeks, 63-fold increased in 1 month and 97-fold increased in volume in 6 weeks. One vessel dilator treated small-cell lung carcinoma animal developed a large tumour (8428 mm3 volume) on treatment and this tumour was eliminated with utilizing atrial natriuretic peptide and then long acting natriuretic peptide sequentially.
Four cardiac hormones eliminate up to 86% of human small-cell lung carcinomas in athymic mice. Urodilatin can also eliminate small-cell lung carcinomas but at a lower cure rate of 25%. Unresponsive lesions can be eliminated by utilizing different hormones synthesized by the atrial natriuretic peptide gene in a sequential manner.
Four cardiac hormones i.e. atrial natriuretic peptide (ANP), vessel dilator, long acting natriuretic peptide (LANP) and kaliuretic peptide have anticancer effects in vitro.
These four cardiac hormones were infused subcutaneously for 28 days with weekly fresh hormones at 3 nM min(-1) kg(-1) body weight in athymic mice bearing human breast adenocarcinomas.
Vessel dilator, LANP, kaliuretic peptide and ANP eliminated 67%, 50%, 67% and 33% of the HTB-132 human breast adenocarcinomas. LANP eliminated 100% and vessel dilator 1/3 of CRL-2327 breast adenocarcinomas. There was no recurrence of the breast cancers in the primary site and no metastasis except in the ANP-treated group in one year post-treatment. The natriuretic peptide receptors-A and -C were decreased 50% and 31%, respectively, in metastatic versus primary ANP-treated breast adenocarcinomas.
Four cardiac hormones eliminate up to two-thirds of human breast adenocarcinomas in athymic mice.
Mitogen-activated protein (MAP) kinases, also known as extracellular signal-regulated kinases (ERKs), are thought to act at
an integration point for multiple biochemical signals because they are activated by a wide variety of extracellular signals,
rapidly phosphorylated on threonine and tyrosine, and highly conserved. A critical protein kinase lies upstream of MAP kinase
and stimulates the enzymatic activity of MAP kinase. The structure of this protein kinase, denoted MEK1, for MAP kinase or
ERK kinase, was elucidated from a complementary DNA sequence and shown to be a protein of 393 amino acids (43,500 daltons)
that is related most closely in size and sequence to the product encoded by the Schizosaccharomyces pombe byr1 gene. The MEK
gene was highly expressed in murine brain, and the product expressed in bacteria phosphorylated the ERK gene product.
The effects on guanylate cyclase and cyclic GMP accumulation of a synthetic peptide containing the amino acid sequence and biological activity of atrial natriuretic factor (ANF) were studied. ANF activated particulate guanylate cyclase in a concentration- and time- dependent fashion in crude membranes obtained from homogenates of rat kidney. Activation of particulate guanylate cyclase by ANF was also observed in particulate fractions from homogenates of rat aorta, testes, intestine, lung, and liver, but not from heart or brain. Soluble guanylate cyclase obtained from these tissues was not activated by ANF. Trypsin treatment of ANF prevented the activation of guanylate cyclase, while heat treatment had no effect. Accumulation of cyclic GMP in kidney minces and aorta was stimulated by ANF activation of guanylate cyclase. These data suggest a role for particulate guanylate cyclase in the molecular mechanisms underlying the physiological effects of ANF such as vascular relaxation, natriuresis, and diuresis.
Mitogen-activated protein (MAP) kinases are serine/threonine protein kinases activated by dual phosphorylation on threonine and tyrosine residues. A MAP kinase kinase (MKK1 or MEK1) has been identified as a dual-specificity protein kinase that is sufficient to phosphorylate MAP kinases p42mapk and p44mapk on the regulatory threonine and tyrosine residues. Because of the multiplicity of MAP kinase isoforms and the diverse circumstances and agonists leading to their activation, we thought it unlikely that a single MKK could accommodate this complexity. Indeed, two protein bands with MKK activity have previously been identified after renaturation following sodium dodecyl sulfate-polyacrylamide gel electrophoresis. We now report the molecular cloning and characterization of a second rat MAP kinase kinase cDNA, MKK2. MKK2 cDNA contains an open reading frame encoding a protein of 400 amino acids, 7 residues longer than MKK1 (MEK1). The amino acid sequence of MKK2 is 81% identical to that of MKK1, but nucleotide sequence differences occur throughout the aligned MKK2 and MKK1 cDNAs, indicating that MKK2 is the product of a distinct gene. MKK1 and MKK2 mRNAs are expressed differently in rat tissues. Both cDNAs when expressed in COS cells displayed the ability to phosphorylate and activate p42mapk and p44mapk, both MKK1 and MKK2 were activated in vivo in response to serum, and both could be phosphorylated and activated by the v-Raf protein in vitro. However, differences between MKK1 and MKK2 in sites of phosphorylation by proline-directed protein kinases predict differences in feedback regulation.
Four cardiac hormones have anticancer effects in vitro: i) atrial natriuretic peptide (ANP), ii) vessel dilator, iii) long acting natriuretic peptide (LANP), and iv) kaliuretic peptide.
These cardiac hormones were infused subcutaneously for 28 days with weekly fresh hormones at 3 nM min(-1) kg(-1) body weight in athymic mice bearing human pancreatic adenocarcinomas.
ANP, vessel dilator, LANP and kaliuretic peptide eliminated 80%, 33%, 20% and 14% of the pancreatic adenocarcinomas. Even in the treated animals which did not have a total cure, their tumor volume decreased to less than 10% (and with vessel dilator to 2%) of that of the untreated animals. The natriuretic peptide receptor (NPR)-A receptor was decreased 33% to 55% in the metastatic lesions compared to the primary pancreatic adenocarcinoma.
Four cardiac hormones eliminated up to 80% of human pancreatic adenocarcinomas in athymic mice.
Summary Ovarian cancer has the highest mortality rate among all gynecological malignancies with an estimated 20,180 new cases and 15,310 deaths in the United States in 2006. Thus, for every four women diagnosed with ovarian cancer there were three deaths from ovarian cancer in 2006 in the United States. Four hormones synthesized by one gene in the heart i.e. atrial natriuretic peptide (ANP), vessel dilator, long acting natriuretic peptide (LANP), and kaliuretic peptide were evaluated with dose response (1 to 100 ∝M) experiments for the ability to decrease the number of human ovarian carcinoma cells in vitro and their DNA synthesis. There was an 81%, 74%, 71%, 70% and 53% increase in cancer cell death of ovarian adenocarcinoma cells within 24 hours secondary to vessel dilator, kaliuretic peptide, ANP, LANP, and their intracellular mediator cyclic GMP, respectively (each at 100 ∝M) (p
A long-term tissue culture cell line has been derived from a human prostate adenocarcinoma metastatic to the brain. The cell line, DU 145, has been passaged 90 times in vitro over a period of 2 years. The cells are epithelial, grow in isolated islands on plastic Petri dishes, and form colonies in soft agar suspension culture. Karyotypic analysis demonstrates an aneuploid human karyotype with a modal chromosome number of 64. Distinctive marker chromosomes (a translocation Y chromosome, metacentric minute chromosomes and three large acrocentic chromosomes) have been identified. Electron microscopy of the original tumor tissue and of the tissue culture cell line show a remarkable similarity in cell organelle structure.
Intracellular communication and transmission of messages for many hormones and free radicals occur after the hormones and free radicals bind to their receptors by enhancing the activity of guanylate cyclase, the enzyme that catalyzes the conversion of guanosine triphosphate to the intracellular messenger cyclic guanosine-3'-5' monophosphate (cyclic GMP). The guanylate cyclase-linked receptors exist intracellularly (ie, cytoplasmic) and in membrane-bound forms. Enhancement of guanylate cyclase by hormones or free radicals increases intracellular cyclic GMP, which closes cation channels in the kidney while activating cation channels in the retina and olfactory cilia, either directly or by cyclic GMP-dependent protein kinase. Cyclic GMP also has potent blood pressure lowering properties. Cyclic GMP promotes growth by increasing DNA, RNA, and protein synthesis. Overactivity of this system is observed in Traveler's diarrhea, whereas underactivity occurs in Chediak-Higashi syndrome in which lysosomal enzyme release and chemotaxis are defective and can be corrected in vitro by addition of cyclic GMP.
Long-acting natriuretic peptide, vessel dilator, kaliuretic peptide and atrial natriuretic peptide are four peptide hormones synthesized by the same gene. Their main known biologic properties are sodium and water excretion and blood pressure lowering in both animals and humans.
These four peptide hormones, each at their 1-microm concentrations, were evaluated for their ability to decrease the number and/or proliferation of human pancreatic adenocarcinoma cells in culture at 24, 48, 72 and 96 h.
Vessel dilator, long-acting natriuretic peptide, kaliuretic peptide and atrial natriuretic peptide decreased the number of human pancreatic adenocarcinoma cells in culture by 65% (P<0.001), 47% (P<0.01), 37% (P<0.05) and 34% (P<0.05), respectively, within 24 h. This decrease was sustained without any proliferation of the cancer cells occurring in the 3 days following this decrease in number. The mechanism of these peptide hormones' decrease in cancer cell number and antiproliferative effects was a 83% (P<0.001) or greater inhibition of DNA synthesis but not owing to enhanced apoptosis, i.e. programmed cell death. The two known mediators of these peptide hormones' mechanism(s) of action, i.e. cyclic GMP and prostaglandin E2, inhibited DNA synthesis in these adenocarcinoma cells by 51% and 23%, respectively.
Four peptide hormones significantly decrease the number of pancreatic adenocarcinoma cells within 24 h and inhibit the proliferation of these cells for at least 96 h. Their mechanism of doing so is via inhibition of DNA synthesis mediated in part by cyclic GMP.
The atrial natriuretic peptide (ANP) gene synthesizes four cardiovascular hormones, i.e. vessel dilator, long-acting natriuretic peptide, kaliuretic peptide and ANP, which decrease the number of human pancreatic adenocarcinoma cells in culture by 65%, 47%, 37%, and 34%, respectively.
None of the cardiovascular hormones has been investigated to determine whether they inhibit the growth of cancers in vivo. These four hormones were evaluated for their ability to inhibit the growth of human pancreatic adenocarcinomas in athymic mice.
Vessel dilator (139 ng min(-1) kg(-1) of body weight) infused for 14 days completely stopped the growth of human pancreatic adenocarcinomas in athymic mice (n = 14) with a decrease in their tumour volume, while the tumour volume increased 69-fold (P < 0.001) in the placebo (n = 30)-treated mice. When these peptide hormones (each at 1.4 microg min(-1) kg(-1) body weight) were infused for 4 weeks, vessel dilator, long-acting natriuretic peptide and kaliuretic peptide decreased tumour volume after 1 week by 49%, 28%, and 11%, respectively, with a one- and 20-fold increase in the tumour volume in ANP- and placebo-treated mice. Cyclic GMP (2.4 microg min(-1) kg(-1) body weight) inhibited after 1 week the growth of this cancer 95%.
These results suggest that these peptide hormones have useful anticancer properties, as they each inhibited the growth of the human pancreatic adenocarcinomas in vivo and three of the four peptide hormones decreased the volume of the tumours (up to 49%, i.e. vessel dilator). Part of their mechanism of action appears to be mediated by cyclic GMP.
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.
Within 24 h four peptide hormones, i.e. vessel dilator, long acting natriuretic peptide, kaliuretic peptide, and atrial natriuretic peptide and their intracellular mediator cyclic GMP decreased the number of human squamous lung cancer cells 51, 22, 25, 21, and 30%, respectively. There was not any proliferation in the 3 days following this decrease in cell number. Vessel dilator decreased DNA synthesis 85% in the squamous lung cancer cells. Thus, vessel dilator significantly decreased the number of human squamous lung cancer cells and their DNA synthesis, mediated in part by cyclic GMP, more than other peptide hormones.
Four peptide hormones of a family of six hormones, i.e. atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-natriuretic peptide (CNP), long acting natriuretic peptide (LANP), vessel dilator and kaliuretic peptide, significantly decrease the number of adenocarcinoma cells in culture. The present investigation was designed to determine whether these peptide hormones' effects are specific to adenocarcinomas or whether they might decrease the number of cancer cells of a different type of cancer, i.e. small-cell lung cancer.
These six hormones were evaluated for their ability to decrease the number and/or proliferation of human small-cell lung cancer cells in culture for 24, 48, 72, and 96 h.
Within 24 h, vessel dilator, LANP, kaliuretic peptide, ANP and their intracellular mediator cyclic GMP, each at 1 microM, decreased the number of small-cell lung cancer cells by 63% (P < 0.001), 21% (P < 0.05), 30% (P < 0.05), 39% (P < 0.05), and 31% (P < 0.05), respectively. There was no proliferation in the 3 days following this decrease in cell number. These same hormones decreased DNA synthesis 68% to 82% (P < 0.001). Brain natriuretic peptide and CNP did not decrease the number of small-cell lung cancer cells or inhibit their DNA synthesis at 1 microM or 10 microM concentrations. Dose-response curves revealed that at 100 microM, the vessel dilator decreased 92% of the cancer cells in 24 h while BNP had no effect, but CNP caused a 39% decrease. Western blots revealed that the natriuretic peptide receptors A- and C- were present in these cancer cells.
Five peptide hormones significantly decrease the number of human small-cell lung cancer cells within 24 h and inhibit their proliferation for at least 96 h. Their mechanism of doing so involves inhibition of DNA synthesis mediated in part by cyclic GMP.
Cell transformation is often a result of constitutive activation of genes in signaling pathways that regulate cell proliferation and differentiation. Indeed, the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway is constitutively activated in a large number of cancers. The extent to which a single-gene mutation can alter cell fate, however, remains questionable. In vitro studies have addressed this issue, but organs are comprised of multiple cell types, and in vitro models often poorly approximate these interactions. In response to these limitations, cell-type specific mouse models have been generated as a means to examine the effect of altering a single element of the MAPK pathway in vivo. This review summarizes data from transgenic murine and human tissue models expressing constitutive active forms of MEK1.
Mortality from prostate cancer remains a significant problem with current treatment(s), with an expected 30 350 deaths from prostate cancer in 2005. Long-acting natriuretic peptide, vessel dilator, kaliuretic peptide and atrial natriuretic peptide have significant anticancer effects in breast and pancreatic adenocarcinomas. Whether these effects are specific and whether they have anticancer effects in prostate adenocarcinoma cells has not been determined.
These peptide hormones were evaluated to determine if they have specific anticancer effects in human prostate adenocarcinomas.
Dose-response curves revealed a significant (P < 0.05) decrease in human prostate cancer number with each tenfold increase in the concentration from 1 microM to 1000 microM (i.e. 1 mM) of these four peptide hormones. There was a 97.4%, 87%, 88% and 89% (P < 0.001 for each) decrease in prostate cancer cells secondary to vessel dilator, long-acting natriuretic peptide, kaliuretic peptide and atrial natriuretic peptide, respectively, at their 1-mM concentrations within 24 h, without any proliferation in the 3 days following this decrease. These same hormones decreased DNA synthesis from 68% to 89% (P < 0.001). When utilized with their respective antibodies their ability to decrease prostate adenocarcinoma cells or inhibit their DNA synthesis was completely blocked. Western blots revealed that for the first time natriuretic peptide receptors (NPR) A- and C- were present in prostate cancer cells.
These results indicate that these peptide hormones' anticancer effects are specific. Furthermore, they have very potent effects of eliminating up to 97% of prostate cancer cells within 24 h of treatment.
Mortality from colon cancer is significant with an expected 30,350 colon cancer deaths in 2005 with current treatment(s). Long-acting natriuretic peptide, vessel dilator, kaliuretic peptide, and atrial natriuretic peptide have significant anticancer effects in breast and pancreatic adenocarcinomas.
Whether these peptide hormones have anticancer effects in colon adenocarcinoma cells and whether these effects are specifically mediated by cyclic GMP has not been determined.
These peptide hormones were evaluated for anticancer effects in human colon adenocarcinoma cells and to determine whether their anticancer effects are specifically mediated by cyclic GMP.
There was a 89-97% decrease (p <0.001 for each) in colon adenocarcinoma cells within 24 h with 1 mM of these peptide hormones. There was a significant (p <0.05) decrease in human colon cancer cell number with each 10-fold increase in concentration from 1 to 1,000 microM (i.e., 1 mM) of these four peptide hormones without any proliferation in the 3 d following this decrease. These same hormones decreased DNA synthesis 65-83% (p <0.001). Cyclic GMP antibody inhibited 75- 80% of these peptides' ability to decrease colon adenocarcinoma cell number and inhibited 92-96% of their DNA synthesis effects and 97% of cyclic GMP's effects. Western blots revealed that for the first time natriuretic peptide receptors (NPR) A and C were present in colon adenocarcinoma cells.
Four peptide hormones eliminate up to 97% of colon cancer cells within 24 h with their DNA effects specifically mediated by cyclic GMP.
The Ras/Raf/MEK/ERK and PI3K/PTEN/AKT signaling cascades play critical roles in the transmission of signals from growth factor receptors to regulate gene expression and prevent apoptosis. Components of these pathways are mutated or aberrantly expressed in human cancer (e.g., Ras, B-Raf, PI3K, PTEN, Akt). Also, mutations occur at genes encoding upstream receptors (e.g., EGFR and Flt-3) and chimeric chromosomal translocations (e.g., BCR-ABL) which transmit their signals through these cascades. These pathways interact with each other to regulate growth and in some cases tumorigenesis. For example, in some cells, PTEN mutation may contribute to suppression of the Raf/MEK/ERK cascade due to the ability of elevated activated Akt levels to phosphorylate and inactivate Raf-1. We have investigated the genetic structures and functional roles of these two signaling pathways in the malignant transformation and drug resistance of hematopoietic, breast and prostate cancer cells. Although both of these pathways are commonly thought to have anti-apoptotic and drug resistance effects on cells, they display different cell-lineage-specific effects. Induced Raf expression can abrogate the cytokine dependence of certain hematopoietic cell lines (FDC-P1 and TF-1), a trait associated with tumorigenesis. In contrast, expression of activated PI3K or Akt does not abrogate the cytokine dependence of these hematopoietic cell lines, but does have positive effects on cell survival. However, activated PI3K and Akt can synergize with activated Raf to abrogate the cytokine dependence of another hematopoietic cell line (FL5.12) which is not transformed by activated Raf expression by itself. Activated Raf and Akt also confer a drug-resistant phenotype to these cells. Raf is more associated with proliferation and the prevention of apoptosis while Akt is more associated with the long-term clonogenicity. In breast cancer cells, activated Raf conferred resistance to the chemotherapeutic drugs doxorubicin and paclitaxel. Raf induced the expression of the drug pump Mdr-1 (a.k.a., Pgp) and the Bcl-2 anti-apoptotic protein. Raf did not appear to induce drug resistance by altering p53/p21Cip-1 expression, whose expression is often linked to regulation of cell cycle progression and drug resistance. Deregulation of the PI3K/PTEN/Akt pathway was associated with resistance to doxorubicin and 4-hydroxyl tamoxifen, a chemotherapeutic drug and estrogen receptor antagonist used in breast cancer therapy. In contrast to the drug-resistant breast cancer cells obtained after overexpression of activated Raf, cells expressing activated Akt displayed altered (decreased) levels of p53/p21Cip-1. Deregulated expression of the central phosphatase in the PI3K/PTEN/Akt pathway led to breast cancer drug resistance. Introduction of mutated forms of PTEN, which lacked lipid phosphatase activity, increased the resistance of the MCF-7 cells to doxorubicin, suggesting that these lipid phosphatase deficient PTEN mutants acted as dominant negative mutants to suppress wild-type PTEN activity. Finally, the PI3K/PTEN/Akt pathway appears to be more prominently involved in prostate cancer drug resistance than the Raf/MEK/ERK pathway. Some advanced prostate cancer cells express elevated levels of activated Akt which may suppress Raf activation. Introduction of activated forms of Akt increased the drug resistance of advanced prostate cancer cells. In contrast, introduction of activated forms of Raf did not increase the drug resistance of the prostate cancer cells. In contrast to the results observed in hematopoietic cells, Raf may normally promote differentiation in prostate cells which is suppressed in advanced prostate cancer due to increased expression of activated Akt arising from PTEN mutation. Thus in advanced prostate cancer it may be advantageous to induce Raf expression to promote differentiation, while in hematopoietic cancers it may be beneficial to inhibit Raf/MEK/ERK-induced proliferation. These signaling and anti-apoptotic pathways can have different effects on growth, prevention of apoptosis and induction of drug resistance in cells of various lineages which may be due to the expression of lineage-specific factors.
Mortality from renal-cell cancer remains a significant problem with an estimated 12,600 deaths in the United States in 2005 even with current treatment(s) of surgery, chemotherapy, radiation and immunotherapy. Four cardiac natriuretic peptides, that is, atrial natriuretic peptide, vessel dilator, long-acting natriuretic peptide and kaliuretic peptide have significant anti-cancer effects in breast, pancreatic, prostate and colon adenocarcinomas.
These four peptide hormones plus brain natriuretic peptide (BNP), C-natriuretic peptide (CNP) and urodilatin, a peptide hormone formed in the kidney by a different post-translational processing of the atrial natriuretic peptide prohormone, were evaluated for their anti-cancer effects in renal carcinomas.
Dose-response curves revealed a significant (P < 0.0001) decrease in human renal carcinoma cells with each 10-fold increase in concentration from 1 microm to 100 microm of five of these peptide hormones. There was an 81%, 74%, 66%, 70% and 70% elimination within 24 h in renal carcinoma cells secondary to vessel dilator, kaliuretic peptide, urodilatin, atrial natriuretic peptide and long-acting natriuretic peptide, respectively (P < 0.0001 for each), whereas BNP had no effect and CNP decreased renal cancer cell number by 10% (P = 0.04) at their 100 microm concentrations. Three days after treatment with these peptide hormones, the cancer cells began to proliferate again. The four cardiac hormones and urodilatin decreased DNA synthesis from 65-84% (P < 0.00001), whereas BNP and CNP decreased DNA synthesis 3% and 12% (both non-significant). Western blots revealed for the first time natriuretic peptide receptors (NPR)-A, -B and -C were present in the renal cancer cells.
These results indicate that urodilatin and the four cardiac hormones have potent anti-cancer effects by eliminating up to 81% of renal carcinoma cells within 24 h of treatment.
There will be an estimated 59,940 new cases of melanoma and 8,110 deaths from melanoma in the United States in 2007. There has been no improvement in survival with melanomas in the last 22 years, with current treatment indicating that new treatment(s) of melanoma are drastically needed. Four cardiac hormones ie, atrial natriuretic peptide, vessel dilator, long-acting natriuretic peptide, and kaliuretic peptide, have significant anticancer effects in adenocarcinomas.
Dose-response curves evaluated the effects of these cardiovascular hormones on cell death and DNA synthesis in several melanoma cell lines in culture for 96 hours. Receptors to mediate these peptide hormones effects were examined in the melanoma cells with Western blots. Their intracellular mediator-analog 8-bromo-cyclic GMP was used to determine if it could mimic their effects on decreasing melanoma cell number and DNA synthesis.
The four cardiac hormones caused cell death in up to 71% (P < 0.001) of the melanoma cells within 24 hours. Cardiac hormone receptors (NPR-A, -B, -C) were present on the melanoma cells, and each of the peptide hormones decreased DNA synthesis within the melanoma cells up to 73% (P < 0.001) at their 1-microM concentrations. 8-Bromo-cyclic GMP mimicked their effects, decreasing the number of melanoma cells up to 67% and their DNA synthesis by 58% (both at P < 0.01).
These results indicate that 4 cardiac hormones have potent beneficial effects by increasing cell death in up to 71% of melanoma cells within 24 hours mediated in part by a 73% decrease in their DNA synthesis.
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