Cytotoxicity of Cholesterol Oxides and the Consequences of Relative Molecular Similarity to cGMP Nucleotide

Abstract

Cholesterol and cholesterol oxides impact on the functional properties of cells, in respect of the intracellular and extracellular distribution of compounds across cell membranes, carcinogenesis and drug resistance. Abnormal levels of cholesterol oxides and steroids in cancerous tissues promote interest in steroid receptor cross-talk during cell-signalling and the steroid metabolome of cancer patients. The research literature links the cytotoxic properties of oxysterols to interference with the NO/cGMP pathway. cGMP participates in cell-signalling and has a molecular structure that relates to cancer-inducing and cancer-preventing agents. This study uses a molecular modelling approach to compare the structures of cholesterol oxides to cGMP. Cholesterol and cholesterol oxide structures fit to a cGMP structural template in several ways, some of which are replicated by corticosteroids and gonadal steroid hormones. The results of this study support the concept that cholesterol oxides modulate cell apoptosis and autophagy via the NO/cGMP pathway and in conjunction with steroid hormones participate in modulating regulation of cell function by cGMP.