Four cardiac hormones eliminate 4-fold more human glioblastoma cells than the green mamba snake peptide

Abstract

Within 24 h four cardiac hormones, i.e., vessel dilator, kaliuretic peptide, atrial natriuretic peptide, and long acting natriuretic peptide decrease the number of human glioblastoma cells 75%, 68%, 67%, and 65% while Dendroaspis (green mamba) peptide caused a 17% decrease when each were utilized at 100 μM. The four cardiac hormones decreased DNA synthesis 65–87% and increased cyclic GMP 1.3- to 3.8-fold in the glioblastoma cells. Natriuretic peptide receptors (NPR)-A and -C were present. Conclusion: four cardiac hormones eliminate up to 75% of glioblastoma cells via cyclic GMP-mediated up to 87% decrease in DNA synthesis.

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.