The broad-spectrum antitumor action of cyclosporin A is due to its tachykinin receptor antagonist pharmacological profile.
Cyclosporin A (CsA) is an immunosuppressive drug. In human cancer cells substance P (SP) and neurokinin-1 (NK-1) receptor antagonists, respectively, induce cell proliferation and inhibition. CsA is a tachykinin receptor antagonist that showed selectivity for both NK-1 and NK-2 receptors. CsA exerts antitumor action against gastric (AGS) and colon (HT29) carcinoma cell lines. However, the mechanisms involved in this action remain unknown, and it is unknown whether CsA exerts an antitumor action on other human cancer cell lines or not. To demonstrate that CsA exerts a broad-spectrum antitumor action, we carried out an in vitro study of the growth-inhibitory capacity of CsA against seven human cancer cell lines, namely GAMG glioma, SKN-BE(2) neuroblastoma, WERI-Rb-1 retinoblastoma, HEp-2 larynx carcinoma, CAPAN pancreas carcinoma, 23132/87 gastric carcinoma, and SW-403 colon carcinoma. A Coulter counter was used to determine viable cell numbers followed by application of the MTS colorimetric method. Micromolar concentrations of CsA inhibited the growth of these tumor cells, both with and without previous administration of nanomolar concentrations of SP; the inhibition occurred in a dose-dependent manner. Moreover, CsA blocks SP-induced mitogen stimulation of tumor cells, suggesting that the NK-1 receptor is involved in such action. Following administration of CsA apoptosis was observed in the above seven tumor cell lines. These findings suggest that the antitumor action of CsA is at least due to its NK-1 receptor antagonist pharmacological profile, since the involvement of NK-2 receptors in the mentioned action must not be discarded, and that CsA has a broad-spectrum antitumor action.
Muñoz
Miguel
M
Virgen del Rocío University Children's Hospital, Sevilla, Spain. mmunoz@cica.es
Rosso
Marisa
M
González
Ana
A
Saenz
Javier
J
Coveñas
Rafael
R
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology* / Q000633:toxicity; D057809:HEK293 Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000633:toxicity; D020128:Inhibitory Concentration 50; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000473:pathology; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1 / Q000819:agonists; D018039:Receptors, Tachykinin / Q000819:agonists / Q000037:antagonists & inhibitors*; D013373:Substance P / Q000037:antagonists & inhibitors / Q000494:pharmacology
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D018039:Receptors, Tachykinin; D013373:Substance P; D016572:Cyclosporine