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Small Molecule Antagonists of the -1 Receptor Cause Selective Release of the Death Program in Tumor and Self-Reliant Cells and Inhibit Tumor Growth in Vitro and in Vivo

Departments of ¹ Surgery and Molecular Oncology and ² Pharmacology and Neuroscience, The University of Dundee, Ninewells Hospital and Medical School, Dundee; Divisions of ³ Cell Signalling and ⁴ Cell Biology and Immunology, School of Life Sciences, The University of Dundee, Dundee; and ⁵ Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, McElwain Laboratories, Surrey, United Kingdom

The acquisition of resistance to apoptosis, the cell’s intrinsic suicide program, is essential for cancers to arise and progress and is a major reason behind treatment failures. We show in this article that small molecule antagonists of the -1 receptor inhibit tumor cell survival to reveal caspase-dependent apoptosis. antagonist-mediated caspase activation and cell death are substantially attenuated by the prototypic -1 agonists (+)-SKF10,047 and (+)-pentazocine. Although several normal cell types such as fibroblasts, epithelial cells, and even receptor-rich neurons are resistant to the apoptotic effects of antagonists, cells that can promote autocrine survival such as lens epithelial and microvascular endothelial cells are as susceptible as tumor cells. Cellular susceptibility appears to correlate with differences in receptor coupling rather than levels of expression. In susceptible cells only, antagonists evoke a rapid rise in cytosolic calcium that is inhibited by -1 agonists. In at least some tumor cells, antagonists cause calcium-dependent activation of phospholipase C and concomitant calcium-independent inhibition of phosphatidylinositol 3'-kinase pathway signaling. Systemic administration of antagonists significantly inhibits the growth of evolving and established hormone-sensitive and hormone-insensitive mammary carcinoma xenografts, orthotopic prostate tumors, and p53-null lung carcinoma xenografts in immunocompromised mice in the absence of side effects. Release of a receptor-mediated brake on apoptosis may offer a new approach to cancer treatment.

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