Four cardiac hormones eliminate 4-fold more human glioblastoma cells than the green mamba snake peptide
Introduction
In 2007, there will be an estimated 20,500 new cases of brain tumors and estimated 12,740 deaths [1]. Gliomas are the most common primary tumors arising from the central nervous system and of the gliomas the most common form (and the most aggressive) is glioblastoma multiforme [2], [3]. At present with surgery, chemotherapy, and radiation the survival of the most aggressive of the primary tumors of the brain, i.e., glioblastoma multiforme (WHO grade IV) is only 50 weeks [4]. Less than 2% of patients survive 3 years post diagnosis [5]. Less than 30% of malignant gliomas respond to adjunct chemotherapy [6], [7]. The epidermal growth factor receptor is frequently overexpressed or mutated in glioblastomas, but only 10–20% respond to epidermal growth factor receptor kinase inhibitors [7]. It is important to note in this regard that the “response” referred to above was not that the tumor was eliminated or decreased in volume but rather that the tumor did not grow more than 25% [7]. In each of the “response” patients the glioblastomas began to grow again in approximately 3 months [7]. “Survival has not improved significantly for multiforme glioblastoma with all of the current treatments and older adults rarely live longer than a year” [2]. There is an obvious need for new adjunct therapy for glioblastomas.
Cardiac natriuretic hormones are a family of peptide hormones that have significant anticancer effects on some cancer cells and tumors [8], [9], [10], [11], [12], [13], [14]. Of this family of peptide hormones, one gene in the heart synthesizes a 126 amino acid (a.a.) prohormone which with proteolytic processing results in four peptide hormones consisting of (1) the first 30 a.a. of this prohormone (i.e., long acting natriuretic peptide, LANP), (2) vessel dilator (vdl, a.a. 31–67), (3) kaliuretic peptide (kp, a.a. 79–98), and (4) atrial natriuretic peptide (ANP, a.a. 99–126) of the 126 a.a. prohormone (Fig. 1). None of these cardiac hormones have ever been investigated on any tumor in the brain or in any portion of the central nervous system. The four peptide hormones synthesized by the cardiac gene were evaluated for their effects on the most common of the central nervous system tumors, i.e., glioblastomas [2], [3]. In addition, a peptide which has been isolated from the venom of the green mamba snake and termed Dendroaspis Natriuretic Peptide (DNP) [15] may have anticancer effects also since it has a similar structure and amino acids to ANP. This peptide has never been examined for its anticancer effects. The four cardiac hormones and DNP were evaluated for their ability to decrease glioblastoma cell number, inhibit DNA synthesis in human glioblastoma cells, and investigated to determine if receptors were present on the glioblastoma cells to mediate atrial natriuretic peptide’s effects.
Section snippets
Human glioblastoma cells
Human glioblastoma cells (ATCC number CRL-11543) were purchased from American Type Culture Collection (ATCC, Manassas, VA). These glioblastoma cells were deposited by the Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA. These glioblastoma cells produce angiogenesis inhibiting factor [16].
Culture of the human glioblastoma cells
Propagation of these human glioblastoma cells was in Dulbecco’s modified Eagle’s medium with 4 mM l-glutamine adjusted to contain 1.5 g/L sodium bicarconate and 4.5 g/L
Decrease in number of human glioblastoma cells by four peptide hormones synthesized by the cardiac ANP gene
The number of human glioblastoma cells in culture for 24 h decreased 53%, 60%, and 75% (down to 33 ± 2 cancer cells from 130 ± 3 cells) secondary to vessel dilator at its 1, 10, and 100 μM concentrations, respectively (p < 0.0001 for each) (Fig. 2). Dose–response curves revealed that LANP in culture for 24 h decreased the number of glioblastoma cells 31%, 49%, and 65% (decreased to 43 ± 2 cancer cells) at its 1, 10, and 100 μM concentrations, respectively (p < 0.001 for each) (Fig. 2). Exposure of the human
Discussion
This is the first investigation of Dendroaspis natriuretic peptide [DNP, 15] as a potential anticancer agent. DNP, isolated from the green mamba snake’s venom, had no significant anticancer effects at it’s 1 and 10 μM concentrations where the other four peptides decreased the average number of glioblastoma cells by 37% and 53%, respectively. At 100 μM, DNP had anticancer effects decreasing the number of glioblastoma cells by 17% which was markedly less (p < 0.001) than the ability of the four
Acknowledgements
We thank Charlene Pennington for excellent secretarial assistance. This work is supported in part by Merit Review Grants from the United States Department of Veterans Affairs (D.L.V. and W.R.G.).
References (33)
- et al.
Vessel dilator: most potent of the atrial natriuretic peptides in decreasing the number and DNA synthesis of squamous lung cancer cells
Cancer Lett.
(2006) - et al.
A new member of the natriuretic peptide family is present in the venom of the green mamba (Dendroaspis augusticeps)
J. Biol. Chem.
(1992) - et al.
Plasma concentration and urinary excretion of N-terminal proatrial natriuretic peptides in patients with kidney diseases
Kidney Int.
(2001) - et al.
Cancer Statistics
CA Cancer. J. Clin.
(2007) - et al.
Primary neoplasms of the central nervous system
- et al.
Long-term survival in patients with supratentorial glioblastoma
J. Neurooncol.
(1998) - et al.
Long-term survivors of glioblastoma: Statistical aberration or important unrecognized molecular subtype?
Cancer J.
(2003) - et al.
Predicting chemoresistance in human malignant glioma cells: the role of molecular genetic analyses
Int. J. Cancer
(1998) - et al.
Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors
N. Engl. J. Med.
(2005)
Four peptides decrease the number of human pancreatic adenocarcinoma cells
Eur. J. Clin. Invest.
Four peptide hormones decrease the number of human breast adenocarcinoma cells
Eur. J. Clin. Invest.
Five cardiac hormones decrease the number of human small-cell cancer cells
Eur. J. Clin. Invest.
Four peptide hormones specific decrease (up to 97%) of human prostate carcinoma cells
Eur. J. Clin. Invest.
Four peptides decrease human colon adenocarcinoma cell number and DNA synthesis via guanosine 3′, 5′-cyclic monophosphate
Int. J. Gastrointest. Cancer
Novel therapeutic approach for cancer using four cardiovascular hormones
Eur. J. Clin. Invest.
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