This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Crawford, K. W. Articles by Bowen, W. D. Search for Related Content PubMed PubMed Citation Articles by Crawford, K. W. Articles by Bowen, W. D.

Sigma-2 Receptor Agonists Activate a Novel Apoptotic Pathway and Potentiate Antineoplastic Drugs in Breast Tumor Cell Lines¹

Howard University College of Medicine, Department of Pharmacology, Washington, DC 20059 [K. W. C.], and Unit on Receptor Biochemistry and Pharmacology, Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892 [W. D. B.]

We have reported previously that sigma-2 receptors are expressed in high densities in a variety of tumor cell types (B. J. Vilner et al., Cancer Res., 55: 408–413, 1995) and that various sigma ligands have cytotoxic effects (B. J. Vilner et al., J. Neurosci., 15: 117–134, 1995). Other investigators have demonstrated increased expression of sigma-2 receptors in rapidly proliferating tumors (R. H. Mach et al., Cancer Res., 57: 156–161, 1997) and the ability of some sigma ligands to inhibit proliferation (P. J. Brent and G. T. Pang, Eur. J. Pharmacol., 278: 151–160, 1995). We demonstrate here the ability of sigma-2 receptor agonists to induce cell death by a mechanism consistent with apoptosis. In breast tumor cell lines that are sensitive (MCF-7) and resistant (MCF-7/Adr-, T47D, and SKBr3) to antineoplastic agents, incubation with the sigma-2 subtype-selective agonists CB-64D and CB-184 produced dose-dependent cytotoxicity (measured by lactate dehydrogenase release into medium). The EC₅₀ for this response was similar across cell lines, irrespective of p53 genotype and drug-resistance phenotype. CB-64D and the subtype nonselective sigma-2 agonists haloperidol and reduced haloperidol induced terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining in MCF-7 and T47D cells, indicating that cell death occurs via apoptosis. Apoptosis was also indicated by increases in Annexin V binding caused by CB-64D. In MCF-7 cells, cytotoxicity and Annexin V binding induced by the antineoplastics doxorubicin and actinomycin D was partially or completely abrogated by certain specific and general inhibitors of caspases. In contrast, caspase inhibitors had no effect on sigma-2 receptor-mediated (CB-64D and CB-184) cytotoxicity or Annexin V binding. Marked potentiation of cytotoxicity was observed when a subtoxic dose of CB-184 was combined with doxorubicin or actinomycin D, both in drug-sensitive (MCF-7) and drug-resistant (MCF-7/Adr-) cell lines. Haloperidol potentiated doxorubicin only in drug-resistant cells. These findings suggest the involvement of a novel p53- and caspase-independent apoptotic pathway used by sigma-2 receptors, which is distinct from mechanisms used by some DNA-damaging, antineoplastic agents and other apoptotic stimuli. These observations further suggest that sigma-2 receptors may be targets that can be therapeutically exploited in the treatment of both drug-sensitive and drug-resistant metastatic tumors.

This article has been cited by other articles:

				A. A. Rybczynska, R. A. Dierckx, K. Ishiwata, P. H. Elsinga, and A. van Waarde Cytotoxicity of {sigma}-Receptor Ligands Is Associated with Major Changes of Cellular Metabolism and Complete Occupancy of the {sigma}-2 Subpopulation J. Nucl. Med., December 1, 2008; 49(12): 2049 - 2056. [Abstract] [Full Text] [PDF]

				A. van Waarde, K. Shiba, J. R. de Jong, K. Ishiwata, R. A. Dierckx, and P. H. Elsinga Rapid Reduction of {sigma}1-Receptor Binding and 18F-FDG Uptake in Rat Gliomas After In Vivo Treatment with Doxorubicin J. Nucl. Med., August 1, 2007; 48(8): 1320 - 1326. [Abstract] [Full Text] [PDF]

				C. Zeng, S. Vangveravong, J. Xu, K. C. Chang, R. S. Hotchkiss, K. T. Wheeler, D. Shen, Z.-P. Zhuang, H. F. Kung, and R. H. Mach Subcellular Localization of Sigma-2 Receptors in Breast Cancer Cells Using Two-Photon and Confocal Microscopy Cancer Res., July 15, 2007; 67(14): 6708 - 6716. [Abstract] [Full Text] [PDF]

				A. Azzariti, N. A. Colabufo, F. Berardi, L. Porcelli, M. Niso, G. M. Simone, R. Perrone, and A. Paradiso Cyclohexylpiperazine derivative PB28, a {sigma}2 agonist and {sigma}1 antagonist receptor, inhibits cell growth, modulates P-glycoprotein, and synergizes with anthracyclines in breast cancer. Mol. Cancer Ther., July 1, 2006; 5(7): 1807 - 1816. [Abstract] [Full Text] [PDF]

				A. van Waarde, P. L. Jager, K. Ishiwata, R. A. Dierckx, and P. H. Elsinga Comparison of Sigma-Ligands and Metabolic PET Tracers for Differentiating Tumor from Inflammation J. Nucl. Med., January 1, 2006; 47(1): 150 - 154. [Abstract] [Full Text] [PDF]

				M. S. Ostenfeld, N. Fehrenbacher, M. Hoyer-Hansen, C. Thomsen, T. Farkas, and M. Jaattela Effective Tumor Cell Death by {sigma}-2 Receptor Ligand Siramesine Involves Lysosomal Leakage and Oxidative Stress Cancer Res., October 1, 2005; 65(19): 8975 - 8983. [Abstract] [Full Text] [PDF]

				A. Mukherjee, T. K. Prasad, N. M. Rao, and R. Banerjee Haloperidol-associated Stealth Liposomes: A POTENT CARRIER FOR DELIVERING GENES TO HUMAN BREAST CANCER CELLS J. Biol. Chem., April 22, 2005; 280(16): 15619 - 15627. [Abstract] [Full Text] [PDF]

				L. Wang, A. R. Prescott, B. A. Spruce, J. Sanderson, and G. Duncan Sigma Receptor Antagonists Inhibit Human Lens Cell Growth and Induce Pigmentation Invest. Ophthalmol. Vis. Sci., April 1, 2005; 46(4): 1403 - 1408. [Abstract] [Full Text] [PDF]

				A. Renaudo, V. Watry, A.-A. Chassot, G. Ponzio, J. Ehrenfeld, and O. Soriani Inhibition of Tumor Cell Proliferation by {sigma} Ligands Is Associated with K+ Channel Inhibition and p27kip1 Accumulation J. Pharmacol. Exp. Ther., December 1, 2004; 311(3): 1105 - 1114. [Abstract] [Full Text] [PDF]

				A. van Waarde, A. R. Buursma, G. A.P. Hospers, K. Kawamura, T. Kobayashi, K. Ishii, K. Oda, K. Ishiwata, W. Vaalburg, and P. H. Elsinga Tumor Imaging with 2 {sigma}-Receptor Ligands, 18F-FE-SA5845 and 11C-SA4503: A Feasibility Study J. Nucl. Med., November 1, 2004; 45(11): 1939 - 1945. [Abstract] [Full Text] [PDF]

				E. Aydar, C. P. Palmer, and M. B. A. Djamgoz Sigma Receptors and Cancer: Possible Involvement of Ion Channels Cancer Res., August 1, 2004; 64(15): 5029 - 5035. [Abstract] [Full Text] [PDF]

				B. A. Spruce, L. A. Campbell, N. McTavish, M. A. Cooper, M. V. L. Appleyard, M. O'Neill, J. Howie, J. Samson, S. Watt, K. Murray, et al. 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 Res., July 15, 2004; 64(14): 4875 - 4886. [Abstract] [Full Text] [PDF]

				Y. Wang, X. Li, L. Wang, P. Ding, Y. Zhang, W. Han, and D. Ma An alternative form of paraptosis-like cell death, triggered by TAJ/TROY and enhanced by PDCD5 overexpression J. Cell Sci., March 15, 2004; 117(8): 1525 - 1532. [Abstract] [Full Text] [PDF]

				L. X. Zhu, S. Sharma, B. Gardner, B. Escuadro, K. Atianzar, D. P. Tashkin, and S. M. Dubinett IL-10 Mediates Sigma1 Receptor-Dependent Suppression of Antitumor Immunity J. Immunol., April 1, 2003; 170(7): 3585 - 3591. [Abstract] [Full Text] [PDF]

				J.-G. Castaigne, W. Guo, C. Leveille, D. Charron, and R. Al-Daccak A CD18-dependent protein kinase C {beta}-mediated alternative cell death pathway of activated monocytes Int. Immunol., September 1, 2002; 14(9): 1003 - 1014. [Abstract] [Full Text] [PDF]

				G. E. Bertolesi, C. Shi, L. Elbaum, C. Jollimore, G. Rozenberg, S. Barnes, and M. E. M. Kelly The Ca2+ Channel Antagonists Mibefradil and Pimozide Inhibit Cell Growth via Different Cytotoxic Mechanisms Mol. Pharmacol., August 1, 2002; 62(2): 210 - 219. [Abstract] [Full Text] [PDF]