title: 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.
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.
authors.affiliation: Department of Surgery and Molecular Oncology, The University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, UK. b.a.spruce@dundee.ac.uk
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Spruce
authors.forename: Lorna A
authors.initials: LA
authors.lastname: Campbell
authors.forename: Niall
authors.initials: N
authors.lastname: McTavish
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Cooper
authors.forename: M Virginia L
authors.initials: MV
authors.lastname: Appleyard
authors.forename: Mary
authors.initials: M
authors.lastname: O'Neill
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Howie
authors.forename: Jayne
authors.initials: J
authors.lastname: Samson
authors.forename: Stephen
authors.initials: S
authors.lastname: Watt
authors.forename: Karen
authors.initials: K
authors.lastname: Murray
authors.forename: Doris
authors.initials: D
authors.lastname: McLean
authors.forename: Nick R
authors.initials: NR
authors.lastname: Leslie
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Safrany
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Ferguson
authors.forename: John A
authors.initials: JA
authors.lastname: Peters
authors.forename: Alan R
authors.initials: AR
authors.lastname: Prescott
authors.forename: Gary
authors.initials: G
authors.lastname: Box
authors.forename: Angela
authors.initials: A
authors.lastname: Hayes
authors.forename: Bernard
authors.initials: B
authors.lastname: Nutley
authors.forename: Florence
authors.initials: F
authors.lastname: Raynaud
authors.forename: C Peter
authors.initials: CP
authors.lastname: Downes
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Lambert
authors.forename: Alastair M
authors.initials: AM
authors.lastname: Thompson
authors.forename: Suzanne
authors.initials: S
authors.lastname: Eccles
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D020013:Calcium Signaling / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002417:Cattle; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005029:Ethylenediamines / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D054803:Phospholipase C delta; D010879:Piperazines / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D010738:Type C Phospholipases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000097605:Sigma-1 Receptor
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D020169:Caspases; D005029:Ethylenediamines; D006220:Haloperidol; D007527:Isoenzymes; D054803:Phospholipase C delta; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017480:Receptors, sigma; D010738:Type C Phospholipases; D000097605:Sigma-1 Receptor; C093337:1-(2-(3,4-dichlorophenyl)ethyl)-4-methylpiperazine; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; C034931:rimcazole