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Inhibition of Phorbol Ester Stimulated Interleukin 2 Production by Copper(II) Complexes¹

Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908 [J. R. H., J. J. S.], and Department of Chemistry, University of North Carolina at Charlotte, Charlotte, North Carolina 28223 [D. P. R., J. H. H.]

Superoxide dismutase mimetic copper(II) complexes, such as copper(II)(3,5-diisopropylsalicylate)₂ (CuDIPS), inhibit phorbol ester stimulated tumor promotion in mouse skin. Therefore, CuDIPS was tested as a potential inhibitor of another effect of phorbol esters, induction of interleukin 2 (IL2) synthesis, in the mouse thymoma cell line EL4. CuDIPS inhibited phorbol ester induced IL2 production in a concentration dependent manner with a 50% inhibitory concentration of about 10 µM. However, the ligand 3,5-diisopropylsalicylic acid also inhibited the induction of IL2 by phorbol esters (50% inhibitory concentration, 15 µM). Since the superoxide dismutase mimetic activity of CuDIPS is not stable in the presence of ethylenediaminetetraacetic acid, the effects of CuDIPS could be due to the free ligand and not to the intact metallocomplex. Consequently, a series of extremely stable copper(II) macrocyclic compounds was synthesized, and the reduction potential, superoxide dismutase mimetic activity, and ability to inhibit phorbol ester induced IL2 production were determined for each. Of the copper(II) macrocyclic complexes studied, only the most potent superoxide dismutase mimetic compound was found to inhibit phorbol ester induced IL2 production. Copper(II) complexes had to be added no later than 4 h following phorbol ester administration to be effective inhibitors of the IL2 response, suggesting that these compounds act subsequent to the binding of phorbol esters but prior to the transcription of IL2 messenger RNA. Adherence of EL4 cells to substrate in response to phorbol esters was unaffected by copper(II) compounds. In summary, copper(II) compounds with appropriate reduction potentials can act within a defined time period to inhibit some, but not all, of the effects of phorbol esters on EL4 cells.

¹ This work was supported by NIH Grant GM 31184, by an award from Eli Lilly, and by the Foundation of the University of North Carolina at Charlotte.

² Predoctoral fellow supported by NIH Grant T32 GM 07055. To whom requests for reprints should be addressed.

³ Recipient of American Cancer Society Grant JFRA 82.

Received 12/10/85. Revised 7/10/86. Accepted 8/ 5/86.