Somatostatin analog SMS 201995 inhibits proliferation in human leukemia T-cell line: relevance of the adenylyl cyclase stimulation.
Octreotide SMS 201995 is a stable somatostatin (SRIF) analog with potent antiproliferative actions in numerous cell types including normal T lymphocytes. It is currently used in the clinical treatment of different malignancies. However, the possible beneficial actions of octreotide in T-cell leukemia have not been addressed before, although these cells express SRIF receptors. For instance, human leukemia Jurkat T cells have been shown to express a single SRIF receptor isotype: sst3 that can be pharmacologically targeted by octreotide. In this study, we therefore studied SMS 201995 effects on in vitro [(3)H-CH3]thymidine incorporation in Jurkat T cells. Our data show that octreotide inhibits the proliferation of Jurkat cells both in the absence and in the presence of mitogens. By contrast, SRIF28, an endogenous SRIF analog sharing with SMS 201995 an almost identical affinity for somatostatin sst3 receptors, increases [(3)H-CH3]thymidine uptake in both mitogen-activated and nonactivated cells. To assess the mechanisms of the opposite actions of these two analogs on leukemia T-cell proliferation, we next studied their effects on adenylyl cyclase activity in whole Jurkat cells. At least in the presence of mitogens, SMS 201995 significantly enhances the adenylyl cyclase activity whereas SRIF28 inhibits it. Taken together these data are in accordance with the current hypothesis according to which increase and decrease in cAMP production are required to allow the inhibition and stimulation of T-cell proliferation, respectively. They also point to a potential therapeutic benefit of SMS 201995 in the management of human T-cell leukemia.
Giannetti
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N
Laboratoire de Biologie Moléculaire et Cellulaire, UMR 49, Ecole Normale Supérieure, Lyon, Cédex 07, France.
Enjalbert
A
A
Krantic
S
S
D000262:Adenylyl Cyclases / Q000378:metabolism*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000201:enzymology*; D008213:Lymphocyte Activation; D015282:Octreotide / Q000494:pharmacology*; D020033:Protein Isoforms; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D053561:Somatostatin-28; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D020033:Protein Isoforms; D013004:Somatostatin; D053561:Somatostatin-28; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D015282:Octreotide