Cancer Therapy Vol 4, 253-262, 2006
Cardiac hormones: dramatic anticancer effects
David L. Vesely
Departments of Internal Medicine, Physiology &
Biophysics, Cardiac Hormone Center, University of South Florida Health Sciences
Center and James A. Haley Veterans Medical Center, Tampa, Florida USA
__________________________________________________________________________________
*Correspondence: David L. Vesely, M.D.,
Ph.D., Director, Cardiac Hormone Center, University of South Florida Medical School,
13000 Bruce B. Downs Blvd., Tampa, Florida 33612; Telephone: (813) 972-7624;
Fax: (813) 972-7623; Email: david.vesely@med.va.gov
Key words: Peptide hormones,
guanosine-3Õ,5Õ-cyclic monophosphate, Extracellular Receptor Kinase 1,2,
Nuclear Factor kB, breast, colon, pancreatic
and prostate adenocarcinomas, angiosarcomas, small-cell and squamous cell lung
carcinomas.
Summary
Cardiac
natriuretic hormones 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 atrial natriuretic peptide (ANP)
prohormone are four peptide hormones i.e., 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.
These four peptide hormones decrease up to 97% of human prostate, breast,
pancreatic and colon adenocarcinoma as well as small-cell and squamous cell
lung cancer cells within 24 hours in
vitro. Their effects are specific as demonstrated with their respective
antibodies blocking all of their anticancer effects. These cardiac hormones
mechanism(s) of action involve localizing to the nucleus of cancer cells where
they inhibit 83% or greater of DNA synthesis mediated via the intracellular
messenger cyclic GMP. In addition to strong DNA inhibitory properties, they
inhibit the activation of Extracellular Receptor Kinase (ERK) 1,2, a cancer
growth-promoting peptide, and inhibit activation of an intracellular mediator
of growth, Nuclear Factor Kappa Beta (NFkB). These
peptide hormones effects are even more impressive in vivo. When given subcutaneously via osmotic pumps to athymic
mice with human pancreatic adenocarcinomas they completely stop the growth of
these adenocarcinomas after one week. Vessel dilator, LANP, and kaliuretic
peptide within one week decrease the volume of human pancreatic adenocarcinomas
by 49%, 28% and 11%.
I. Introduction: cardiac peptide hormones
Cardiac natriuretic peptide hormones consist of a
family of peptide hormones that are synthesized by three different genes and
then stored as three different prohormones [i.e., 126 amino acid (a.a.) atrial
natriuretic peptide (ANP), 108 a.a. brain natriuretic peptide (BNP), and 103
a.a. C-type natriuretic peptide (CNP) prohormones] (Brenner et al, 1990;
Gardner et al, 1997). Within the 126 a.a. ANP prohormone are four peptide
hormones (Figure 1) whose main known
biologic properties are blood pressure regulation and maintenance of plasma
volume in animals (Martin et al, 1990; Gunning et al, 1992; Benjamin and
Peterson, 1995; Ziedel, 1995; Villarreal et al, 1999; Dietz et al, 2001) and
humans (Vesely et al, 1994 a,b, 1998). These peptide hormones, numbered by
their a.a. sequences beginning at the N-terminal end of the ANP prohormone,
consist of the first 30 a.a. of the prohormone i.e., long acting natriuretic
peptide (LANP), a.a. 31-67 (vessel dilator), a.a. 79-98 (kaliuretic peptide)
and a.a. 99-126 (ANP) (Vesely 1992; 2002). The BNP and CNP genes, on the other
hand, appear to each synthesize only one peptide hormone within their
respective prohormones, i.e., BNP and CNP (Gardner et al, 1997; Lainchbury et
al, 1997; Scotland et al, 2005). Each of these peptide hormones circulates in
healthy humans with vessel dilator and LANPÕs concentrations in plasma being
17- to 24-fold higher than ANP, 33 to 48-fold higher than BNP and 124 to
177-fold higher than CNP (Winters et al, 1989; Vesely et al, 1989; Hunter et
al, 1998; DePalo et al, 2000; Franz et al, 2000, 2001; Vesely, 2003).
ANP has growth-regulatory properties (Toshimori et al,
1987; Abell et al, 1989; Itoh et al, 1990, 1992). In vascular smooth muscle,
ANP inhibits cell proliferation (hyperplasia) as well as smooth muscle cell
growth (hypertrophy) (Toshimori et al, 1987; Abell et al, 1989; Itoh et al, 1990,
1992). Atrial natriuretic peptide has growth-regulatory properties in a variety
of other tissues including brain, bone, myocytes, red blood cell precursors,
and endothelial cells (Johnson et al, 1998; Appel, 1988, 1990, 1992; Haneda et
al, 1993; Pedram et al, 1997; Yu et al, 1997; Calderone et al, 1998). In the
kidney, ANP causes antimitogneic and antiproliferative effects in glomerular
mesangial cells (Appel 1988, 1990, 1992; Haneda et al, 1993).
Figure. 1. Atrial natriuretic peptide (ANP) gene synthesizes a
126 amino acid (a.a.) prohormone which contains four peptide hormones
consisting of amino acids 1-30 (i.e., long acting natriuretic peptide, LANP)
a.a. 31-67 (vessel dilator), a.a. 79-98 (kaliuretic peptide) and atrial
natriuretic peptide (ANP, a.a. 99-126 of this prohormone). Reproduced from
Vesely et al, 2006 with kind permission from Atrial Natriuretic Hormones, 1st
Edition 1992, Pearson Education, Inc., Upper Saddle River, NJ.
II. Cardiac natriuretic hormones decrease the number and DNA synthesis
of human pancreatic adenocarcinomas
The first cancer studied both in vitro and in vivo was
human pancreatic adenocarcinomas which have the lowest 5-year survival rate of
all common cancers (Pitchumoni, 1998; Wolff et al, 2000). The 5-year survival
rate of persons with adenocarcinoma of the pancreas is 1% with a median
survival of only four months (Pitchumoni, 1998; Wolff et al, 2000). Current
cancer chemotherapy and surgery prolong survival by a few months but the
above-mentioned survival rates are for persons treated with surgery and/or
current cancer chemotherapeutic agents (Pitchumoni, 1998; Wolff et al, 2000).
Vessel dilator, LANP, kaliuretic peptide and ANP (each
at a relatively low concentration of 1 mM) decrease the number of human pancreatic adenocarcinoma cells in
culture by 65% (P<0.001), 47% (P<0.01), 37% and 34% (both at P<0.05),
respectively, within 24 hours (Vesely et al, 2003). This decrease was sustained
without any proliferation of the adenocarcinoma cells occurring in the three days
following this decrease in number (Vesely et al, 2003). Thus, when exposed to
vessel dilator, LANP, kaliuretic peptide and ANP for 48 hours the inhibition of
the number of cancer cells compared to controls was 68% (P<0.001), 43%, 40%
and 33% (P<0.05 for these three peptides), respectively (Vesely et al,
2003). At both 72 hours and 96 hours, the decrease in number of adenocarcinoma
cells secondary to vessel dilator was 70% (P<0.001) (Vesely et al, 2003).
LANP for 72 and 96 hours resulted in the number of adenocarcinoma cells being
reduced 47% and 48% (P<0.01 for both), respectively (Vesely et al, 2003). At
72 and 96 hours, the number of cancer cells with kaliuretic peptide present was
decreased by 39% and 42% compared to untreated control cells (P<0.05 for
each) (Vesely et al, 2003). The number of adenocarcinoma cells at 72 and 96
hours was decreased secondary to ANP by 37% and 35% (P<0.05 for both)
(Vesely et al, 2003). At least part of the mechanism of these peptide hormonesÕ
decrease in cancer cell number and antiproliferative effects was a 83% or
greater inhibition of DNA synthesis (Vesely et al, 2003). Thus, vessel dilator,
LANP, kaliuretic peptide and ANP each at their 1 mM concentrations inhibited DNA synthesis when
incubated with adenocarcinoma cells for 24 hours by 91%, 84%, 86% and 83%,
respectively (P<0.001 for each). One of the known mediators (Waldman et al,
1984; Vesely 1997) of these peptide hormonesÕ mechanism(s) of action, i.e.,
cyclic GMP, inhibited DNA synthesis in these adenocarcinoma cells by 51%.
Dose-response curves revealed that 8-bromo- cyclic GMP, the cell permeable
analog of cyclic GMP, decreased DNA synthesis in these cancer cells 46%, 42%,
39%, and 34% (all P<0.05) at its 3 mM, 1 mM, 100 mM, and 1 mM concentrations, respectively (Vesely et al, 2003). Even at 1 nM
(i.e., 10-9 M) of 8-bromo-cyclic GMP there was a 25% decrease in DNA
synthesis in the adenocarcinoma cells (P<0.05) (Vesely et al, 2003). At 100
pM of 8-bromo cyclic GMP, its effects on DNA synthesis in these adenocarcinoma
cells became not significant (14% decrease).
III. Cardiac natriuretic hormones stop the growth of human pancreatic
adenocarcinomas in vivo
In vivo, these peptide hormonesÕ effects as anticancer agents
were even more impressive. Vessel dilator (139 ng/min/kg of body weight)
infused subcutaneously for 14 days via osmotic pumps completely stopped the
growth of human pancreatic adenocarcinomas in athymic mice (n=14) with a
decrease in their tumor volume, even when the tumor volume was large i.e.,
60-fold increase in size over basal palpable tumor before peptide infusion was
begun, to mimic what occurs in humans, i.e., the pancreatic adenocarcinomas in
humans are usually large before they are discovered (Vesely et al, 2004). The
tumor volume increased 69-fold in this two-week period (P<0.001) when
measured with electronic Vernier calipers in the placebo (n=30)-treated mice
(Vesely et al, 2004). Dose-response studies revealed that at concentrations as
low as 1.7 ng/ min/20 gram mouse, vessel dilator could completely stop the
growth of the human pancreatic adenocarcinomas, but at this concentration there
was no decrease in the volume of the tumor by vessel dilator (Vesely et al,
2004). The tumor volume of the untreated human pancreatic adenocarcinoma
increased 172-fold in three weeks and was almost 300-fold increased four weeks
after the tumors first became palpable (Vesely et al, 2004). After two months,
the volume of this untreated aggressive adenocarcinoma was 1306-fold greater
than when the tumors first became palpable (Vesely et al, 2004). When these
peptide hormones at 10-fold higher concentrations (i.e., at 1.4 mg/min/kg body weight) were infused for four weeks, in
addition to completely stopping the growth of this aggressive adenocarcinoma,
vessel dilator, long acting natriuretic peptide and kaliuretic peptide
decreased human pancreatic adenocarcinomasÕ tumor volume after one week by 49%,
28%, and 11%, respectively, with a one- and 20-fold increase in the tumor
volume in ANP- and placebo-treated mice (Vesely et al, 2004). Cyclic GMP (0.05 mg/ min/20 gram mouse body weight) inhibited after one
week the growth of this cancer 95% (Vesely et al, 2004). There was no evidence
of cytotoxicity in any of the normal tissues during the infusion of these
peptide hormones.
IV.
Localization of the cardiac natriuretic hormones within the human pancreatic
adenocarcinomas
Immunocytochemical evaluation after removal of the
human pancreatic adenocarcinomas revealed that vessel dilator, LANP, kaliuretic
peptide and ANP each localized to the nucleus and cytoplasm of the cancer cells
and to the endothelium of the capillaries growing into these tumors (Figure 2) (Saba et al, 2005). These
cardiac hormones also localized to the fibroblasts within the adenocarcinomas (Figure 2) (Saba et al, 2005). This
investigation was the first demonstration of any anti-growth peptide hormone
localizing to the nucleus where they could directly inhibit DNA synthesis (Saba
et al, 2005). It is, thus, of interest that all four of these peptide hormones,
which inhibit DNA synthesis, localized to the nucleus. Growth promoting
peptides such as Extracellular Receptor Kinase (ERK)-1 have been shown to move
from the plasma membrane to the nucleus to cause proliferation. A slightly
modified kaliuretic peptide for nanotechnology can substantially decrease the
activation ERK-1/2 (Mohapatra et al, 2004). These peptide hormones may, thus,
inhibit the growth of cancer cells not only by directly inhibiting DNA
synthesis in the nucleus but by also decreasing the activation of growth
promoting substances like ERK-1/2 which promote the growth of cancer cells
(Mohapatra et al, 2004).
Figure 2. Immunoperoxidase
localization of vessel dilator, LANP, kaliuretic peptide, and ANP within human
pancreatic adenocarcinomas with each of these peptide hormones strongly
localizing to cytoplasm (Cy), nucleus (N),
endothelium (E), and fibroblasts (F). The light blue stain in the
fibroblasts is the nuclei of the fibroblasts. (A) Vessel dilator treated, (B)
LANP treated, (C) kaliuretic peptide
treated, and (D) ANP treated.
Primary antibody of each peptide was diluted 1:800. Original magnification x
60. The inset in (A) is an isolated
nuclei illustrating that vessel dilator has immunoperoxidase staining within
the nucleus. The inset in (D) is a
negative control using the human pancreatic adenocarcinoma with substitution of
the primary antibodies with normal rabbit serum. Reproduced from Saba et al,
2006 with kind permission from Journal of Histochemistry and Cytochemistry.
V.
Four cardiac hormones eliminate up to 97% of human prostate, breast and colon
adenocarcinoma cells as well as small-cell and squamous carcinoma of the lung
cells
Dose-response curves have revealed that there is a
significantly greater (P<0.05) decrease in the number of cancer cells at
each 10-fold increase in concentration of the four peptide hormones synthesized
by the ANP gene in human breast, colon, and prostate adenocarcinomas as well as
in small-cell and squamous carcinoma of the lung cells (Vesely et al, 2005a,b,c,
2006; Gower et al, 2005). Table 1 is
an example of this with colon adenocarcinoma cells. At 1 mM of these respective
hormones up to 97% of the above human cancer cells were eliminated, i.e., only
3 to 4 ± 0.6 cells were not killed. Thus, with vessel dilator nearly all of the
human cancer cells were eliminated (Vesely et al, 2005a,b,c, 2006; Gower et al,
2005). In several fields there were no cancer cells at all, i.e., vessel
dilator had killed 100% of the cancer cells within 24 hours. In none of the human
cancers is there a proliferation of the remaining cancer cells after the
initial decrease in cancer cell number secondary to these peptide hormones.
Dose-response investigations have further revealed that brain natriuretic
peptide (BNP) has no anticancer effects in any concentration and that CNP, from
the third cardiac gene, has anticancer effects only at 100-fold higher
concentrations than that observed with the above four cardiac hormones (Vesely
et al, 2005a,b,c, 2006; Gower et al, 2005).
VI. Elimination of human breast adenocarcinomas in vivo
We have infused subcutaneously 100 mM and 1 mM of vessel dilator and LANP for
four weeks with a weekly change in the osmotic pumps in athymic mice harboring
human breast adenocarcinomas. After three weeks, in the majority of the mice,
the human breast cancers disappeared and no evidence of breast cancer was
present in any tissue or organ at necropsy two months later (BA Vesely, et al.
unpublished observation). There were no side effects of the 100 mM or 1 mM concentrations of these peptide
hormones in vivo during their one
month of infusion or in the two months post-infusion follow-up (BA Vesely, et
al, unpublished observation).
Cell-cycle progression was directly affected by
several of the cardiac hormones. The majority of the cardiac hormones had their
strongest modification of cell-cycle progression in the synthetic (S) phase of
the cell cycle. Vessel dilator, long acting natriuretic peptide, kaliuretic
peptide and 8-bromo-cyclic GMP (each at 1 mM) decreased the number of breast cancer cells in the S phase of the
cell cycle by 62%, 33%, 50%, and 39%, respectively (all P<0.05) (Vesely et
al, 2005b). ANP caused a 40% decrease in the G2-M proliferative
phase the cell cycle. There was an accumulation of cells in the resting G0-G1
phase secondary to LANP, vessel dilator, kaliuretic peptide and ANP (Vesely et
al, 2005b). Vessel dilator, which caused the largest decrease in cells in the S
phase, had the largest accumulation of cells in the G0-G1
phase (Vesely et al, 2005b). BNP had no effect on the S phase or any other
portion of the cell cycle (Vesely et al, 2005b).
VIII. Natriuretic peptide receptors (NPR) A and C are
present in human cancers
Each of the human cancer cells listed above have
natriuretic peptide receptors to mediate these peptide hormonesÕ effects
(Vesely et al, 2005a,b,c, 2006; Gower et al 2005). Thus, when human breast
adenocarcinoma cells were evaluated by Western blots, natriuretic peptide
receptors (NPR)-A and -C were demonstrated to be present (Vesely et al, 2005b).
It is of interest that the breast adenocarcinoma cells have developed an NPR-A-
and -C receptors to mediate ANPÕs effects via membrane-
Table 1. Percent Decrease in Human Colon Adenocarcinoma Cells
Within 24 Hours: Dose-Response Relationships.
|
% Decrease |
|||||||
|
|
|||||||
|
Dose |
Vessel Dilator |
LANP |
Kaliuretic Peptide |
ANP |
BNP |
CNP |
Cyclic GMP |
|
1 mM |
97 |
89 |
89 |
89 |
5 |
6 |
84 |
|
100 mM |
90 |
68 |
72 |
69 |
4 |
4 |
65 |
|
10 mM |
72 |
55 |
55 |
54 |
2 |
3 |
57 |
|
1 mM |
60 |
31 |
30 |
35 |
1 |
1 |
33 |
LANP = Long acting
natriuretic peptide; ANP = Atrial natriuretic peptide, BNP = Brain natriuretic
peptide, CNP = C-natriuretic peptide; Cyclic GMP = cyclic 3Õ,5Õ-guanosine
monophosphate. The decrease in colon cancer cells with 1 mM of vessel dilator,
LANP, kaliuretic peptide, ANP and cyclic GMP was significant at P<0.001
while BNP and CNPÕs effects were not significant when evaluated by repeated
analysis of variance (ANOVA), (n = 60 for each group). Reproduced from Gower et
al Jr, 2005 with kind permission from International Journal of Gastrointestinal
Cancer.
bound
guanylate cyclase which is part of the NPR-A receptor and via NPR-C receptor
mediated mechanisms, respectively. The NPR-C receptor does not contain
guanylate cyclase which catalyzes the formation of the intracellular cyclic
GMP. ANPÕs signaling via the NPR-C receptor is thought to involve a cascade of
Ca2+ influx, activation of endothelial nitric oxide synthase with
resulting formation of nitric oxide activating cytosolic guanylate cyclase,
which in turn, increases the concentration of cyclic GMP (Murthy et al, 1998).
The presence of these receptors helps to explain why ANP, but not BNP and CNP,
has effects at its 1 mM concentration as ANP
binds to both receptors with a stronger affinity than BNP or CNP and, thus, a
lower concentration of ANP is needed to have effects (Vesely et al,
2005a). When the concentrations of
CNP and BNP are increased 100-fold, in dose-response curves, CNP but not BNP has
effects of decreasing the number of cancer cells (Vesely et al, 2005c). This is
consistent with CNPÕs binding to NPR-C receptor with a stronger affinity than
BNP but not as strong as ANP i.e., binding to NPR-C receptors is ANP > CNP
> BNP (Suga et al, 1992).
IX. Cardiac hormones anticancer effects are specific
To determine if the effects of these peptide hormones
to decrease the number of human cancer cells were specific these peptides
hormonesÕ respective antibodies (Ab) were utilized in a 1:5 concentration of
peptide hormone to their respective antibody in the examination of human
prostate adenocarcinomas. When these peptide hormones (each at 1 mM) were incubated with their specific antibodies (5 mM) the decrease in cancer cell number secondary to
vessel dilator alone of 63% (89 ± 2 to 33 ± 2 cancer cells) was
reduced to 2% only (89 ± 2 cells in control vs 87
± 2 cancer cells with Ab plus vessel dilator) (Vesely
et al, 2005a). There was no decrease in cell number with LANP plus its antibody
(89 ± 2 control cancer cells vs 89 ± 2 cells with LANP and Ab) (Vesely et al, 2005a).
Kaliuretic peptide plus its antibody resulted in a 0.4% (89 ± 2 control cells vs 88 ± 2 cancer cells with kaliuretic peptide plus Ab)
decrease versus a 30% decrease (62 ± 3 cells vs 89 ± 2 control cells) with
kaliuretic peptide alone (Vesely et al, 2005a). These antibodies studies also
indicated that ANPÕs effects were specific with the 37% decrease (to 56 ± 3 cells) in cell number with ANP alone decreased to
2% (87 ± 2 cells vs 89 ± 2 control cancer cells) when its antibody was added (Vesely et al,
2005a). The addition of specific antibody blocked each of these peptides
ability to decrease cancer cells at P<0.0001.
When these specificity experiments were extended to
48, 72, and 96 hours of incubation of antibody plus peptide hormones, for
vessel dilator plus antibody, the decrease in number of cancer cells was 1%,
0%, and 1%, respectively (versus untreated control prostate cancer cells at
these three time points) (P<0.0001). LANP plus its antibody resulted in 0%,
1%, 1% decrease in cancer cells at 48, 72, and 96 hours (Vesely et al, 2005a).
With kaliuretic peptide plus its antibody there was a 0%, 0%, and 1% decrease
in prostate cancer cell number at 48, 72, and 96 hours, respectively (Vesely et
al, 2005a). When ANPÕs antibody plus ANP were incubated for 48, 72, and 96
hours there was a 0%, 0%, and 0% decrease in prostate cancer cells at each time
period (Vesely et al, 2005a).
When the antibodies alone (same concentration) were
incubated for 24 hours without the addition of any of the peptide hormones, the
vessel dilator antibody resulted in a 5% increase (rather than decrease) (i.e.,
93.4 ± 1.5 cells vs 88 ± 6 control cancer cells) in prostate cancer cell number while the ANP
antibody resulted in a 3% increase (92 ± 2 cells) in prostate adenocarcinoma cells (Vesely et al, 2005a). With
the LANP and kaliuretic peptide antibodies alone for 24 hours there was a 0%
(89 ± 2 cells) and 2% increase (91 ± 2 cells), respectively versus 89 ± 2 untreated prostate cancer cells (Vesely et al, 2005a).
Thus, there was no significant decrease in cancer number with the antibodies
alone, but rather 3 of the 4 antibodies caused a small increase in cancer cell
number within 24 hours.
X. These cardiac hormonesÕ ability to inhibit DNA synthesis is specifically
mediated by cyclic GMP
With respect to the mechanism of how these peptide
hormones inhibit DNA synthesis, one of the second messengers of their biologic
effects i.e., cyclic GMP was found using 8-bromo-cyclic GMP (1 mM) to inhibit DNA synthesis 57% in the human colon
cancer cells (Gower et al, 2005). Cyclic GMPÕs mimicking the effects of these
peptide hormones on DNA synthesis in the same cells suggests that cyclic GMP is
one of the mediators of these peptide hormonesÕ ability to decrease cancer cell
number and to inhibit DNA synthesis in colon adenocarcinoma cells. This was
further defined when utilizing a cyclic GMP antibody it was demonstrated that
this antibody could essentially block all of cyclic GMPÕs effects on decreasing
colon cancer cell number and DNA synthesis (Gower et al, 2005). Utilizing this
antibody suggests that cyclic GMPÕs effects on cancer cells are specific, i.e.,
not due to some other mediator. Further, the cyclic GMP antibody almost
completely blocked each of the cardiac peptide hormonesÕ ability to inhibit DNA
synthesis which strongly suggests that their ability to inhibit DNA is almost
exclusively mediated by cyclic GMP (Gower et al, 2005).
XI. Mechanism of action of cardiac hormones
decreasing the number of cancer cells
When the cyclic GMP antibody was incubated with vessel
dilator, LANP, kaliuretic peptide and ANP it blocked 75 to 80% of their effects
on decreasing colon cancer number (Gower et al, 2005). This would suggest that
these peptideÕs mechanism(s) of action as anticancer agents is mediated
partially but not completely by cyclic GMP (Gower et al, 2005). This
information is compatible with the information that one of these peptides,
i.e., kaliuretic peptideÕs ability to decrease activation of extracellular
receptor kinase (ERK) 1/2, a cancer growth promoting peptide which translates
from the extracellular membrane to the nucleus of the cell to promote growth
(Mohapatra et al, 2004). Thus, one additional mechanism of these peptidesÕ
antigrowth effects is their ability to decrease the activation of growth
promoting peptides (Mohapatra et al, 2004) as well as directly inhibiting DNA
synthesis within the nucleus (Saba et al, 2005). Kaliuretic peptide and ANP
also significantly decrease the activation of NFkB, an intracellular mediator of growth (Mohapatra et
al, 2004).
XII. Cardiac hormonesÕ effects on sarcomas
These cardiac hormones decrease the number of sarcoma
cells and their DNA synthesis (Vesely et al, 2006) as well as in the cancer
cells outlined above. About one-fourth of all primary cardiac tumors are
malignant and usually are invasive (Colucci and Schoen, 2001). These malignant
tumors of the heart can occur at any age but are most common in the third to
fifth decades of life (Colucci and Schoen, 2001). The malignant tumors of the
heart have an equal incidence in women and men and can occur in children and
infants (Chahinian et al, 2003). The most common primary malignant cardiac
tumors are angiosarcomas (Chahinian et al, 2003). From a clinical standpoint,
primary malignant tumors of the heart cause a rapid downhill course with death
occurring from a few weeks to two years after the onset of symptoms (Donsbeck
et al, 1999; Colucci and Schoen, 2001). Complete surgical resection of cardiac
angiosarcomas is usually impossible (Chahinian et al, 2003). The combination of
surgery followed by radiotherapy and chemotherapy based upon doxorubicin has
resulted in no cures and usually a failure to alter the course leading to death
(Colucci and Schoen, 2001). Within 24 hours, vessel dilator, LANP, kaliuretic
peptide, ANP and their intracellular mediator cyclic GMP each at relatively low
concentration of 1 µM decreased the number of angiosarcoma cells in vitro 61%, 30%, 29%, 36%, and 32%,
respectively, and its DNA synthesis 68% to 85% (Vesely et al, 2006). BNP and
CNP had no effect(s) at the same concentration (Vesely et al, 2006).
XIII. Natriuretic peptides do not have side effects of
current anticancer agents
The above four
cardiovascular peptide hormones do not cause nausea, vomiting, alopecia, or
myleosuppression that is common with current cancer chemotherapy or the more
severe toxicity of permanent ovarian dysfunction and leukemia and/or secondary
tumors that occurs with currently utilized anticancer agents (Pitchumoni 1998;
Wolff et al, 2000). The lack of these side effects and their
beneficial effects of decreasing the number of cancer cells suggests that the
cardiovascular hormones synthesized by the ANP prohormone gene may have use in
the future as anticancer agents.
I thank Darren
Manelski and the Darren Manelski Foundation, New York, New York and the United
States Department of Veterans Affairs for support of this research. I also
thank Charlene Pennington for excellent secretarial assistance.
Abell TJ,
Richards AM, Ikram H, Espiner EA and Yandle T (1989) Atrial natriuretic factor inhibits proliferation of vascular
smooth muscle cells stimulated by platelet derived growth factor. Biochem Biophys Res Commun 160, 1392-1396.
Appel RG (1988) Growth inhibitory activity of
atrial natriuretic factor in rat glomerular mesangial cells. FEBS Lett 238, 135-138.
Appel RG (1990) Mechanism of atrial natriuretic
factor-induced inhibition of rat mesangial cell mitogenesis. Am J Physiol 259, E312-E318.
Appel RG (1992) Growth-regulatory properties of atrial natriuretic factor. Am J Physiol 262, F911-F918.
Benjamin BA,
and Peterson TV (1995) Effects of
proANF (31-67) on sodium excretion in conscious monkeys. Am J Physiol 269, R1351-R1355.
Brenner BM,
Ballermann BJ, Gunning ME, and Zeidel ML (1990)
Diverse biological actions of atrial natriuretic peptide. Physiol Rev 70, 665-699.
Calderone A,
Thaik CM, Takahashi N, Takahashi N, Chang DL, and Colucci WS (1998) Nitric oxide, atrial natriuretic
peptide and cyclic GMP inhibit the growth-promoting effects of norepinephrine
in cardiac myocytes and fibroblasts. J
Clin Invest 101, 812-818.
Chahinian AP,
Gutstein DE, and Fuster V (2003)
Tumors of the heart and great vessels. In: Cancer
Medicine. Kufe DW, Pollock E, Weichselbaum RR, Bast RC Jr, Gansler TS,
Holland JF, Frei E III, editors. BC Decker Inc, Hamilton, Ontario. 1475-1477.
Colucci WS and
Schoen FJ (2001) Primary tumors of
the heart. In: Heart Disease.
Braunward E, Zipes DP, and Libby P, editors. 6th Edition, W.B. Saunders
Co., Philadelphia. pp 1807-1822.
De Palo EF,
Woloszczuk W, Meneghetti M, De Palo CB, Nielsen HB, and Secher NH (2000) Circulating immunoreactive proANP
(1-30) and proANP (31-67) in sedentary subjects and athletes. Clin Chem 46, 843-7.
Dietz JR, Scott
DY, Landon CS, and Nazian SJ (2001)
Evidence supporting a physiological role for proANP (1-30) in the regulation of
renal excretion. Am J Physiol 280, R1510-R1517.
Donsbeck AV,
Ranchere D, Coindre JM, Le Gall F, Cordier JF and Loire R (1999) Primary cardiac sarcomas: an immunohistochemical and grading
study with long-term follow-up. Histopathology
34, 295-304.
Franz M,
Woloszczuk W, and Horl WH (2000)
N-terminal fragments of the proatrial natriuretic peptide in patients before
and after hemodialysis treatment. Kidney
Int 58, 374-378.
Franz M,
Woloszczuk W, and Horl WH (2001)
Plasma concentration and urinary excretion of N-terminal proatrial natriuretic
peptides in patients with kidney diseases. Kidney
Int 59, 1928-1934.
Gardner DG,
Kovacic-Milivojevic BK, and Garmai M (1997)
Molecular biology of the natriuretic peptides. In: Vesely DL, editor. Atrial Natriuretic Peptides.
Trivandrum, India: Research Signpost. pp. 15-38.
Gower WR Jr,
Vesely BA, Alli AA, and Vesely DL (2005)
Four peptides decrease human colon adenocarcinoma cell number and DNA synthesis
via guanosine 3Õ,5Õ-cyclic monophosphate. Int
J Gastrointestinal Cancer 36, 77-87.
Gunning ME,
Brady HR, Otuechere G, Brenner BM, and Ziedel ML (1992) Atrial natriuretic peptide (31-67) inhibits Na transport in
rabbit inner medullary collecting duct cells: Role of prostaglandin E2.
J Clin Invest 89, 1411-1417.
Haneda M,
Kikkawa R, Koya D, Sakamoto K, Nakanishi S, Matsuda Y, and Shigeta Y (1993) Biological receptors mediate
anti-proliferative action of atrial natriuretic peptide in cultured mesangial
cells. Biochem Biophys Res Commun
192, 642-648.
Hunter EFM,
Kelly PA, Prowse C, Woods FJ, and Lowry PJ (1998) Analysis of peptides derived from pro atrial natriuretic
peptide that circulate in man and increase in heart disease. Scan J Clin Lab Invest 58, 205-216.
Itoh H, Pratt
RE, and Dzau VJ (1990) Atrial natriuretic polypeptide
inhibits hypertrophy of vascular smooth muscle cells. J Clin Invest 86, 1690-1697.
Itoh H, Pratt
TE, Ohno M, and Dzau VJ (1992) Atrial natriuretic polypeptide as a
novel antigrowth factor of endothelial cells. Hypertension 19, 758-761.
Johnson A,
Lermioglu F, Garg UC, Morgan-Boyd R, and Hassid A (1988) A novel biological effect of atrial natriuretic hormone:
inhibition of mesangial cell mitogenesis. Biochem
Biophys Res Commun 152, 893-897.
Lainchbury J,
Richards AM, and Nicholls MG (1997)
Brain natriuretic peptide in heart failure In: Vesely DL, editor. Atrial Natriuretic Peptides.
Trivandrum, India: Research Signpost. p. 151-158.
Martin DR,
Pevahouse JB, Trigg DJ, Vesely DL, and Buerkert JE (1990) Three peptides from the ANF prohormone NH2-terminus
are natriuretic and/or kaliuretic. Am J
Physiol 258, F1401-F1408.
Mohapatra SS,
Lockey RF, Vesely DL, and Gower WR Jr (2004)
Natriuretic peptides and genesis of asthma: An emerging paradigm? J Allergy & Clinical Immuol 114,
520-526.
Murthy KS,
Teng B, Jin J, and Makhlouf GM (1998)
G-protein-dependent activation of smooth muscle eNOS via natriuretic peptide
clearance receptor. Am J Physiol
275, C1409-1416.
Pedram A,
Razandi M, Hu RM, and Levin ER (1997)
Vasoactive peptides modulate vascular endothelial cell growth factor production
and endothelial cell proliferation and invasion. J Biol Chem 272, 17097-17103.
Pitchumoni CS
(1998) Pancreatic Disease In: Stein JH ed Internal Medicine, St
Louis: Mosby; 2233-2247.
Saba SR,
Garces AH, Clark LC, Gower WR Jr and Vesely DL (2005) Immunoctyochemical localization of atrial natriuretic
peptide, vessel dilator, long acting natriuretic peptide, and kaliuretic peptide
in human pancreatic adenocarcinomas. J
Histochem Cytochem 53, 989-995.
Scotland RS,
Ahluwalia A, and Hobbs AJ (2005)
C-type natriuretic peptide in vascular physiology and disease. Pharmacol Ther 105, 85-93.
Suga SI, Nakao
K, Hosoda K, Mukoyama M, Ogawa Y, Shirakami G, Arai H, Saito Y, Kambayashi Y,
and Inouye K (1992) Receptor
selectivity of natriuretic peptide family, atrial natriuretic peptide, brain
natriuretic peptide, and C-type natriuretic peptide. Endocrinology 130, 229-239.
Toshimori H,
Toshimori K, Oura C, and Matsuo H (1987) Immunohistochemical study of atrial
natriuretic polypeptides in the embryonic fetal and neonatal rat heart. Cell Tissue Res 248, 627-633.
Vesely BA,
Alli AA, Song S, Gower WR Jr, Sanchez-Ramos J, and Vesely DL (2005a) Four peptide hormones specific
decrease (up to 97%) of human prostate carcinoma cells. Eur J Clin Invest 35, 700-710.
Vesely BA,
Alli A, Song S, Sanchez-Ramos J, Fitz SR, Gower WR Jr, and Vesely DL (2006) Primary malignant tumors of the
heart: Four cardiovascular hormones decrease the number and DNA synthesis of
human angiosarcoma cells. Cardiology
105, 226-33.
Vesely BA,
Fitz SR, Gower WR Jr, and Vesely DL (2006)
Vessel dilator: most potent of the atrial natriuretic peptides in decreasing
the number and DNA synthesis of human squamous lung cancer cells. Cancer Lett 233, 226-31.
Vesely BA,
McAfee Q, Gower WR, Jr, and Vesely DL (2003)
Four peptides decrease the number of human pancreatic adenocarcinoma cells. Eur J Clin Invest 33, 998-1005.
Vesely BA,
Song S, Sanchez-Ramos J, Fitz SR, Solivan SR, Gower Jr, and Vesely DL (2005b) Four peptide hormones decrease
the number of human breast adenocarcinoma cells. Eur J Clin Invest 35, 60-69.
Vesely BA,
Song S, Sanchez-Ramos J, Fitz SR, Alli A, Solivan SR, Gower Jr, and Vesely DL (2005c) Five cardiac hormones decrease
the number of human small-cell lung cancer cells. Eur J Clin Invest 35, 388-398.
Vesely DL (1992) Atrial Natriuretic Hormones.
Englewood Cliffs NJ: Prentice Hall, 1-256.
Vesely DL (1997) Signal transduction: Activation of the guanylate cyclase-cyclic
guanosine-3Õ5Õ monophosphate system by hormones and free radicals. Am J Med Sci 314, 311-323.
Vesely DL (2002) Atrial natriuretic peptide
prohormone gene expression: Hormones and diseases that upregulate its expression.
IUBMB Life 53, 153-159.
Vesely DL (2003) Natriuretic peptides and acute
renal failure. Am J Physiol 285,
F167-F177.
Vesely DL,
Clark LC, Garces AH, McAfee QW, Soto J, and Gower WR Jr (2004) Novel therapeutic approach for cancer using four cardiovascular
hormones. Eur J Clin Invest 34,
674-682.
Vesely DL,
Dietz JR, Parks JR, Baig M, McCormick MT, Cintron G, and Schocken DD (1998) Vessel dilator enhances sodium
and water excretion and has beneficial hemodynamic effects in persons with
congestive heart failure. Circulation
98, 323-329.
Vesely DL,
Douglass MA, Dietz JR, Gower WR Jr, McCormick MT, Rodriguez-Paz G, and Schocken
DD (1994) Three peptides from the
atrial natriuretic factor prohormone amino terminus lower blood pressure and
produce diuresis, natriuresis and/or kaliuresis in humans. Circulation 90, 1129-1140.
Vesely DL,
Douglass MA, Dietz JR, Gower WR Jr, McCormick MT, Rodriguez-Paz G, and Schocken
DD (1994) Negative feedback of
atrial natriuretic peptides. J Clin
Endocrinol Metab 78, 1128-1134.
Vesely DL,
Norris JS, Walters JM, Jespersen RR, and Baeyens DA (1987) Atrial natriuretic prohormone peptides 1-30, 31-67 and 79-98
vasodilate the aorta. Biochem Biophys
Res Commun 148, 1540-1548.
Vesely DL,
Norsk P, Winters CJ, Rico DM, Sallman AL, and Epstein M (1989) Increased release of the N-terminal and C-terminal portions
of the prohormone of atrial natriuretic factor during immersion-induced central
hypervolemia in normal humans. Proc Soc
Exp Biol Med 192, 230-235.
Villarreal D,
Reams GP, Taraben A, and Freeman RH (1999
) Hemodynamic and renal effects of proANF 31-67 in hypertensive rats. Proc Soc Exp Biol Med 221, 166-170.
Waldman SA,
Rapoport RM, and Murad F (1984)
Atrial natriuretic factor selectively activates membranous guanylate cyclase
and elevates cyclic GMP in rat tissues.
J Biol Chem 259, 14332-14334.
Winters CJ,
Sallman AL, Baker BJ, Meadows J, Rico DM, Vesely DL (1989) The N-terminus and a 4000 molecular weight peptide from the
mid portion of the N-terminus of the atrial natriuretic factor prohormone each
circulate in humans and increase in congestive heart failure. Circulation 80, 438-449.
Wolff RA,
Abbruzzese JL, and Evans DB (2000) In: Bast RC Jr, Kufe DW, Pollock RE,
Weichselbaum RR, Holland JF, and Frei III E, eds Cancer Medicine, London:
BC Decker Inc, 1436-1464.
Yu SM, Hung
LM, and Lin CC (1997) cGMP-elevating
agents suppress proliferation of vascular smooth muscle cells by inhibition the
activation of epidermal growth factor signaling pathway. Circulation 95, 1269-1277.
Zeidel ML (1995) Regulation of collecting duct Na+
reabsorption by ANP 31-67. Clin Exp
Pharmacol Physiol 22, 121-124.
David L. Vesely