Small molecule antagonists of the sigma-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 A 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 journalArticle

136 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 sigma-1 receptor inhibit tumor cell survival to reveal caspase-dependent apoptosis. sigma antagonist-mediated caspase activation and cell death are substantially attenuated by the prototypic sigma-1 agonists (+)-SKF10,047 and (+)-pentazocine. Although several normal cell types such as fibroblasts, epithelial cells, and even sigma receptor-rich neurons are resistant to the apoptotic effects of sigma 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 sigma receptor coupling rather than levels of expression. In susceptible cells only, sigma antagonists evoke a rapid rise in cytosolic calcium that is inhibited by sigma-1 agonists. In at least some tumor cells, sigma antagonists cause calcium-dependent activation of phospholipase C and concomitant calcium-independent inhibition of phosphatidylinositol 3'-kinase pathway signaling. Systemic administration of sigma 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 sigma 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 number14
DOIs
Publication statusPublished - 15 Jul 2004

Keywords

  • Animals
  • Antineoplastic Agents
  • Apoptosis
  • Breast Neoplasms
  • Calcium Signaling
  • Carbazoles
  • Caspases
  • Cattle
  • Cell Division
  • Cell Line, Tumor
  • Enzyme Activation
  • Ethylenediamines
  • Haloperidol
  • Humans
  • Isoenzymes
  • Lung Neoplasms
  • Male
  • Mice
  • Mice, Nude
  • Phospholipase C delta
  • Piperazines
  • Prostatic Neoplasms
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Receptors, sigma
  • Type C Phospholipases
  • Xenograft Model Antitumor Assays

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  • Cite this

    Spruce, B. A., Campbell, L. A., McTavish, N., Cooper, M. A., Appleyard, M. V. L., O'Neill, M., Howie, J., Samson, J., Watt, S. A., Murray, K., McLean, D., Leslie, N. R., Safrany, S. T., Ferguson, M. J., Peters, J. A., Prescott, A. R., Box, G., Hayes, A., Nutley, B., ... Eccles, S. (2004). Small molecule antagonists of the sigma-1 receptor cause selective release of the death program in tumor and self-reliant cells and inhibit tumor growth in vitro and in vivo. Cancer Research, 64(14), 4875-4886. https://doi.org/10.1158/0008-5472.CAN-03-3180