Effects of colchicine on cyclic AMP levels in human leukocytes

Abstract

The increase in human leukocyte cyclic[c]AMP levels seen in response to various substances was markedly potentiated by colchicine and other agents that affect microtubule assembly. Addition of dl-isoproterenol (2 .mu.M) or prostaglandin E1 (10 .mu.M), together with the phosphodiesterase inhibitor isobutylmethylxanthine (1 mM), caused a much greater increase in cAMP in colchicine-pretreated cells than in control cells. With isoproterenol (2 .mu.M) plus isobutylmethylxanthine (1 mM), cAMP levels rose about 3-fold but, in combination with colchicine, these drugs caused a > 15-fold increase in cAMP. Effects of colchicine were time- and dose-dependent; they could be seen within 1 min after addition of colchicine or at concentrations as low as 10 nM. In addition to its potentiation of hormonally induced increases in cAMP levels, colchicine potentiated the effect of isobutylmethylxanthine alone on leukocyte cAMP levels. Vinblastine, vincristine, podophyllotoxin and oncodazole all had effects similar to those of colchicine, but lumicolchicine did not. Cytoplasmic microtubules appear to interact with the leukocyte plasma membrane to impose constraints on expression of hormone-sensitive adenylate cyclase; therapeutic effects of colchicine may depend in part upon relaxation of such constraints. The synergism described between colchicine-like agents and hormones is of potential therapeutic importance in clinical conditions in which alkaloid or hormone is useful separately.