title: The anticancer drug Dp44mT inhibits T-cell activation and CD25 through a copper-dependent mechanism.
abstract: The di-2-pyridylketone thiosemicarbazone Dp44mT is a metal-chelating compound that has been demonstrated to have potent activity as an anticancer agent. Here we report that it also has a dramatic inhibitory effect on T-cell activation in vitro. We found that 10 nM Dp44mT (IC(50) 3.2 nM) prevented the up-regulation of surface CD25, and completely suppressed the activation and proliferation of splenic T cells isolated from Mus musculus that were stimulated with either T-cell receptor (TCR) cross-linking antibodies or phorbol ester plus ionomycin. In contrast, Dp44mT had no adverse effects on the survival of resting T cells. In addition, T cells stimulated in the presence of Dp44mT maintained the ability to up-regulate CD69 surface expression and secrete interleukin-2. Consistent with these observations, Dp44mT did not inhibit multiple canonical signals downstream of the TCR, including the nuclear factor of activated T cells. The effects of Dp44mT were easily mitigated by addition of nontoxic copper chelators or N-acetylcysteine, indicating a role for copper and reactive oxygen species in its actions. Together, these findings suggest that Dp44mT may serve as a potent immunosuppressive agent that could complicate its use as a cancer therapeutic agent, but might have utility in the treatment of autoimmunity.
authors.affiliation: Department of Pediatric and Adolescent Medicine, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Justin H
authors.initials: JH
authors.lastname: Gundelach
authors.forename: Ajay A
authors.initials: AA
authors.lastname: Madhavan
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wettstein
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bram
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003300:Copper / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D019169:Jurkat Cells; D037181:Lectins, C-Type / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D061988:Proteasome Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D013882:Thiosemicarbazones / Q000494:pharmacology*; D000099192:CD69 Antigens
chemical_list: D000111:Acetylcysteine; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000970:Antineoplastic Agents; D003300:Copper; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D007501:Iron; D007502:Iron Chelating Agents; D037181:Lectins, C-Type; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D013882:Thiosemicarbazones; D000099192:CD69 Antigens; C508018:Il2ra protein, mouse; C539263:di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone