HISTAMINE H-2-RECEPTOR DESENSITIZATION IN HL-60 HUMAN PROMYELOCYTIC LEUKEMIA-CELLS

Google Scholar
  • 1 January 1984
    • journal article
    • research article
    • Vol. 231  (1) , 1-7
Abstract
Recent studies have suggested that cAMP may be involved in regulation of cell growth and differentiation of cancer cells. Incubating HL-60 cells in the presence of the specific H2 agonist dimaprit resulted in 30-fold increases in cAMP levels (EC50 [median effective concentration] = 5.7 .times. 10-6 M) and morphological changes suggestive of cell maturation along the granulocyte pathway. Cells cultured with 10-5 M dimaprit showed > an 80% decrease in their cAMP response to subsequent addition of H2 agonists, while the cAMP response to prostaglandin E2 was unaltered. Desensitization was time-dependent (halftime .apprx. 2.5 h with 10-5 M dimaprit), dose-dependent (dimaprit EC50 = 1.4 .times. 10-6 M) and completely prevented by 10-3 M cimetidine. Desensitization of HL-60 cells for 4 h with 10-5 M dimaprit followed by the addition of 10-3 M cimetidine resulted in total recovery of the cAMP response in < 24 h. The pharmacologically inactive analog N-methyldimaprit (SK and F 92054) did not increase cAMP production or cause desensitization to H2 stimulation. Desensitization was observed in the presence or absence of a phosphodiesterase inhibitor, indicating that induction of cAMP-phosphodiesterase was not involved in this process. No difference in the number of [3H]tiotidine binding sites was observed between control and dimaprit-desensitized HL-60 cells. Evidently, H2 receptor agonists caused an agonist-dependent desensitization, presumably due to an uncoupling of receptors from adenylate cyclase. Despite the rapid desensitization of the H2 response, dimaprit did induce the cellular maturation of HL-60, suggesting a possible role for endogenous histamine in the regulation of growth and differentiation of the myelogenous cell.