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 Ca2+ 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.