Tumour initiation, store-operated calcium entry (SOCE) and apoptosis: cyclic nucleotide dependence

Abstract

Chemical instigators and modulators of tumourigenesis influence cell signal transduction pathways. Cyclic nucleotides and steroid hormones may contribute to the process of carcinogenesis or provide protection via apoptotic mechanisms. Although several pharmacologic classes of compounds influence cyclic nucleotide levels markedly, less is known about the class effects of promoters and blockers of tumourigenesis and apoptosis. This molecular modeling study uses cyclic nucleotide templates to investigate relative molecular similarity within compounds modulating tumourigenesis and apoptosis. Findings, in respect of superimposition and molecular fit of the investigated compounds, are related to their individual effects on cyclic nucleotide pharmacology. Modulators of tumourigenesis and estrogen receptor sub-type ligands relate to cyclic nucleotide structure. Estradiol and GPER ligands provide a similar pattern of fit to adenine nucleotide. Chemically diverse modulators of apoptosis, including K + channel ligands, fit to different components of cyclic nucleotide structure. Compounds modulating Ca 2+ entry and IP3 receptors relate structurally to the nucleotide dioxaphosphinin moiety. Relative molecular similarity within the structures of apoptosis and tumourigenesis modulators identifies a unifying property within chemically disparate compounds. The ubiquitous generation of oxidative stress and ROS in cells by apoptosis modulating compounds may relate to the disruption of cyclic nucleotide regulated homeostasis mechanisms.

Cyclic Nucleotide Structural Differentiation of Compounds Modulating Apoptosis and Drug Resistance

“…The latter set accommodates the BMM structure (butyl-2methyl-malonic acid) [19], a compound that has found use as a radioactive marker of apoptosis following chemotherapy. The fitting-points of ML-9 [20] and taurine [22] target the same site and differ from those of the other sulphur containing amino acid, homocysteine [21]. Goodness of fit values for Figure 5 structures (n = 22) range from 0.02 -0.14 Å (interatomic distance) and 0.0007 -0.0227 Å (RMS).…”

“…Ca 2+ entry via cGMP activation of cyclic nucleotide-gated channels contributes to mouse rod photoreceptor apoptosis [68]. cGMP inhibits the actions of cyclopiazonic acid and thapsigargin on SOCE [22] and matrix metalloproteinase release implicated in raising the invasive potential of hepatocellular carcinoma cells [69]. Basal levels of cGMP may prevent the development of apoptosis by contributing to the stability of cell membranes [9] [70].…”

“…Many compounds relate to cGMP in respect of molecular similarity and functional properties. cGMP inhibits SOCE activating mechanisms and molecular similarity is evident in SOCE modulators that promote apoptosis in cancer cell lines [22]. Of 40 apoptosis-inducing compounds demonstrating relative molecular similarity to cGMP, 70% also provide protection against apoptosis [22].…”

“…cGMP inhibits SOCE activating mechanisms and molecular similarity is evident in SOCE modulators that promote apoptosis in cancer cell lines [22]. Of 40 apoptosis-inducing compounds demonstrating relative molecular similarity to cGMP, 70% also provide protection against apoptosis [22]. Specific anti-apoptic properties are characteristic of folic acid, vitamin E and phytic acid.…”

Small Molecular Weight Compounds Antagonistic to Amyloid Peptide<sub>25-35</sub>

“…Several classes of cell receptor are susceptible to desensitization, internalisation or activation by Aβ: adrenergic, NMDA and α7-nicotinic acid (α-7nACh) receptors [5] [6]. Aβ fragment Aβ [25][26][27][28][29][30][31][32][33][34][35] , the biologically active region of Aβ, also inhibits glucose uptake in hippocampal neuron cultures via activation of Gs-protein coupled receptors [7].…”