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Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 370, Issue 2, pp 106–113 | Cite as

Antiproliferative and cytotoxic effects of some σ2 agonists and σ1 antagonists in tumour cell lines

  • Nicola Antonio Colabufo
  • Francesco Berardi
  • Marialessandra Contino
  • Mauro Niso
  • Carmen Abate
  • Roberto Perrone
  • Vincenzo Tortorella
Original Article

Abstract

To establish the activity of σ ligands at σ1 and σ2 receptor, we chose two tumour cell lines, the human SK-N-SH neuroblastoma and the rat C6 glioma lines, which express σ2 receptors at a high density and σ1 receptors in their high-affinity or low-affinity state. We tested the σ2 receptor agonist PB28 and the σ2 antagonist AC927, and (+)-pentazocine and NE100 as agonist and antagonist, respectively, at σ1 receptors, with regard to antiproliferative and cytotoxic effects. In addition, 1,3-di(2-tolyl)guanidine (DTG) and haloperidol were tested as reference compounds displaying nearly equipotent σ affinity (σ21 and σ12, respectively). In both SK-N-SH and C6 cells, PB28 and NE100 displayed the most potent results both in antiproliferative and cytotoxic assay while AC927 and (+)-pentazocine were inactive in both assays. The cytotoxic and antiproliferative effects of DTG and haloperidol reflected their σ1 antagonist activity and σ2 agonist activity. Moreover, our results in the tumour cell lines correlated well with those for σ2 activity found previously in a functional assay in the guinea-pig bladder. These findings establish a new model for evaluating both σ2 and σ1 receptor activity of σ ligands, which could be useful for developing new ligands having mixed σ2 agonist/σ1 antagonist activity as potential antineoplastic agents.

Keywords

σ2 Receptor agonist σ1 Receptor antagonist Tumour cell lines PB28 AC927 (+)-Pentazocine NE100 

References

  1. Ablordeppey SY, Fischer JB, Burker Howie KJ, Glennon RA (1992) Design, synthesis and binding of sigma receptor ligands derived from butaclamol. Med Chem Res 2:368–375Google Scholar
  2. Berardi F, Colabufo NA, Giudice G, Perrone R, Tortorella V, Govoni S, Lucchi L (1996) New σ and 5-HT1A receptor ligands: ω-(tetralin-1-yl)-n-alkylamine derivatives. J Med Chem 39:176–182CrossRefPubMedGoogle Scholar
  3. Berardi F, Ferorelli S, Colabufo NA, Leopoldo M, Perrone R, Tortorella V (2001) A multireceptorial binding reinvestigation on an extended class of σ ligands: N-[ω-(indan-1-yl-and tetralin-1-yl)alkyl] derivatives of 3,3-dimethylpiperidine reveal high affinities towards σ1 and EBP sites. Bioorg Med Chem 9:1325–1335CrossRefPubMedGoogle Scholar
  4. Berardi F, Ferorelli S, Colabufo NA, Contino M, Perrone R, Tortorella V (2004) 4-(Tetralin-1-yl- and naphthalen-1-yl)alkyl derivatives of 1-cyclohexylpiperazine as σ receptor ligands with agonist σ2 activity. J Med Chem 47:2308–2317CrossRefPubMedGoogle Scholar
  5. Cavalieres V, Everaert H, Lahoutte T, Dierickx LO, John CS, Bossuyt A (2001) Labeled sigma receptor ligands: can their role in neurology and oncology be extended? Eur J Nucl Med Mol Imaging 28:133–135CrossRefGoogle Scholar
  6. Cheng YC, Prusoff WH (1973) Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 22:3099–3108CrossRefPubMedGoogle Scholar
  7. Colabufo NA, Berardi F, Contino M, Perrone R, Tortorella V (2003) A new method to evaluate σ2 ligands in isolated guinea-pig bladder. Naunyn Schmiedeberg’s Arch Pharmacol 138:106–112CrossRefGoogle Scholar
  8. Crawford KW, Bowen WD (2002) Sigma-2 receptor agonists activate a novel apoptotic pathway and potentiate antineoplastic drugs in breast tumor cell lines. Cancer Res 62:313–322PubMedGoogle Scholar
  9. Crawford KW, Coop A, Bowen WD (2002) σ2 Receptors regulate changes in sphingolipid levels in breast tumor cells. Eur J Pharmacol 443:207–209CrossRefPubMedGoogle Scholar
  10. Crawford KW, Bittman R, Chun J, Byun HS, Bowen WD (2003) Novel ceramide analogues display selective cytotoxicity in drug-resistant breast tumor cell lines compared to normal breast epithelial cells. Cell Mol Biol 49:1017–1023Google Scholar
  11. Elsinga PH, Kawamura K, Kobayashi T, Tsukada H, Senda M, Vaalburg W, Ishiwata K (2002) Synthesis and evaluation of [18F]fluoroethyl SA4503 as a PET ligand for the sigma receptor. Synapse 43:259–267CrossRefPubMedGoogle Scholar
  12. Itzak Y (1994) The sigma receptor (Neuroscience perspective series). Academic Press, LondonGoogle Scholar
  13. John CS, Bowen WD, Saga T, Kimuya S, Vilner BJ, Baumgold J, Paik CH, Reba RC, Neuman RD, Varma VM, McAfee JG (1993) A malignant melanoma imaging agent: synthesis, characterization, in vitro binding and biodistribution of iodine-125-(2-piperidinylaminoethyl)-4-iodobenzamide. J Nucl Med 34:2169–2175PubMedGoogle Scholar
  14. John CS, Vilner BJ, Schwartz AM, Bowen WD (1996) Characterization of sigma receptor binding sites in human biopsied solid breast tumor (abstract). J Nucl Med 37:267PGoogle Scholar
  15. John CS, Gulden ME, Li JH, Bowen WD, McAfee JG, Thakur ML (1998) Synthesis, in vitro binding, and tissue distribution of radioiodinated 2-[125I]N-(N-benzylpiperidin-4-yl)-2-iodobenzamide, 2-[125I]BP: a potential sigma receptor marker for human prostate tumors. Nucl Med Biol 25:189–194CrossRefPubMedGoogle Scholar
  16. Hellewell SB, Bowen WD (1990) A sigma-like binding site in rat pheochromocytoma (PC12) cells: decreased affinity for (+)-benzomorphans and lower molecular weight suggest a different sigma receptor form from that of guinea pig brain. Brain Res 527:244–253CrossRefPubMedGoogle Scholar
  17. Hellewell SB, Bruce A, Feinstein G, Orringer J, Williams W, Bowen WD (1994) Rat liver and kidney contain high densities of sigma-1 and sigma-2 receptors: characterization by ligand binding and photoaffinity labeling. Eur J Pharmacol 268:9–18CrossRefPubMedGoogle Scholar
  18. Kawamura K, Elsinga PH, Kobayashi T, Ishii S, Wang WF, Matsuno K, Vaalburg W, Ishiwata K (2003) Synthesis and evaluation of 11C- and 18F-labeled 1-[2-(4-alkoxy-3-methoxyphemyl)ethyl]-4-(3-phenylpropyl)piperazines as sigma receptor ligands for positron emission tomography studies. Nucl Med Biol 30:273–284CrossRefPubMedGoogle Scholar
  19. Mach RH, Smith CR, al-Nabusi I, Whirrett BR, Childers SR, Wheeler KT (1997) Sigma-2 receptor as potential biomarkers of proliferation in breast cancer. Cancer Res 57:156–161PubMedGoogle Scholar
  20. Maeda DY, Williams W, Bowen WD, Coop A (2000) A sigma-1 receptor selective analogue of BD1008. A potential substitute for (+)-opioids in sigma receptors binding assays. Bioorg Med Chem Lett 10:17–18CrossRefPubMedGoogle Scholar
  21. Matsumoto RR, Bowen WD, Tom MA, Van Nhi V, Truong DD, De Costa B (1995) Characterization of two novel sigma receptor ligands: antidystonic effects in rats suggest sigma receptor antagonism. Eur J Pharmacol 280:301–310CrossRefPubMedGoogle Scholar
  22. Mossman T (1983) Rapid colorimetric assay for cellular growth and survival. J Immunol Methods 65:55–63CrossRefPubMedGoogle Scholar
  23. Nakazato A, Kumagai T, Otha K, Chaki S, Okuyama S, Tomisawa K (1999) Synthesis and SAR of 1-alkyl-2-phenylethylamine derivatives designed from N,N-dipropyl-4-methoxy-3-(2-phenylethoxy)phenylethylamine to discover sigma(1) ligands. J Med Chem 42:3965–3970CrossRefPubMedGoogle Scholar
  24. Perrone R, Berardi F, Colabufo NA, Leopoldo M, Abate C, Tortorella V (2000) N-Aryl- or N-alkylpiperazine derivatives: the role of N-substituent on σ1, σ2, 5-HT1A and D2 receptor afffinity. Med Chem Res 10:201–207Google Scholar
  25. Quirion R, Bowen WD, Itzak Y, Junien JL, Musacchio JM, Rothman RB, Su TP, Taylor DP (1992) A proposal for the classification of sigma binding sites. Trends Pharmacol Sci 13:85–86CrossRefPubMedGoogle Scholar
  26. Tanaka M, Shirasaki T, Kaku S, Muramatsu M, Otomo S (1995) Characteristic of binding of [3H]NE-100, a novel sigma-receptor ligand, to guinea-pig membranes. Naunyn Schmiedeberg’s Arch Pharmacol 351:244–251Google Scholar
  27. Vilner BJ, Bowen WD (2000) Modulation of cellular calcium by sigma-2 receptors: release from intracellular stores in human SK-N-SH neuroblastoma cells. J Pharmacol Exp Ther 292:900–911PubMedGoogle Scholar
  28. Vilner BJ, John CS, Bowen WD (1995a) Sigma-1 and sigma-2 receptors are expressed in a wide variety of human and rodent tumor cell lines. Cancer Res 55:408–413PubMedGoogle Scholar
  29. Vilner BJ, de Costa BR, Bowen WD (1995b) Cytotoxic effects of sigma ligands: sigma receptor-mediated alterations in cellular morphology and viability. J Neurosci 15:117–134PubMedGoogle Scholar
  30. Walker JM, Bowen WD, Walker FO, Matsumoto RR, de Costa BR, Rice KC (1990) Sigma receptors: biology and function. Pharmacol Rev 42:355–402PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Nicola Antonio Colabufo
    • 1
  • Francesco Berardi
    • 1
  • Marialessandra Contino
    • 1
  • Mauro Niso
    • 1
  • Carmen Abate
    • 1
  • Roberto Perrone
    • 1
  • Vincenzo Tortorella
    • 1
  1. 1.Dipartimento Farmaco-ChimicoBariItaly

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