Small molecule antagonists of the σ-1 receptor cause selective release of the death program in tumor and self-reliant cells and inhibit tumor growth in vitro and in vivo

Barbara A. Spruce, Lorna A. Campbell, Niall McTavish, Michelle A. Cooper, M. Virginia L. Appleyard, Mary O'Neill, Jacqueline Howie, Jayne Samson, Stephen Watt, Karen Murray, Doris McLean, Nick R. Leslie, Stephen T. Safrany, Michelle J. Ferguson, John A. Peters, Alan R. Prescott, Gary Box, Angela Hayes, Bernard Nutley, Florence RaynaudC. Peter Downes, Jeremy J. Lambert, Alastair M. Thompson, Suzanne Eccles

    Research output: Contribution to journalArticlepeer-review

    143 Citations (Scopus)

    Abstract

    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 s-1 receptor inhibit tumor cell survival to reveal caspase-dependent apoptosis. s antagonist-mediated caspase activation and cell death are substantially attenuated by the prototypic s-1 agonists (+)-SKF10,047 and (+)-pentazocine. Although several normal cell types such as fibroblasts, epithelial cells, and even s receptor-rich neurons are resistant to the apoptotic effects of s 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 s receptor coupling rather than levels of expression. In susceptible cells only, s antagonists evoke a rapid rise in cytosolic calcium that is inhibited by s-1 agonists. In at least some tumor cells, s antagonists cause calcium-dependent activation of phospholipase C and concomitant calcium-independent inhibition of phosphatidylinositol 3'-kinase pathway signaling. Systemic administration of s 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 s receptor-mediated brake on apoptosis may offer a new approach to cancer treatment.
    Original languageEnglish
    Pages (from-to)4875-4886
    Number of pages12
    JournalCancer Research
    Volume64
    Issue number1
    DOIs
    Publication statusPublished - 2004

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