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Correlation of the Antiproliferative Action of Diphenylmethane-Derivative Antiestrogen Binding Site Ligands with Antagonism of Histamine Binding but not of Protein Kinase C-mediated Phosphorylation¹

Departments of Medicine [L. J. B.], Pharmacology and Therapeutics [L. J. B., F. S. L.], and Pediatrics [J. M. G.], Faculties of Medicine and Pharmacy [R. E. R.], and the Manitoba Institute of Cell Biology [L. J. B., J. M. G., R. P. B., D. W. L.], University of Manitoba, Winnipeg, Manitoba, R3E 0V9 Canada

The nonestrogen receptor-mediated antiproliferative action of antiestrogen binding site (AEBS) ligands, including triphenylethylene antiestrogens and phenothiazines, has been linked to their ability to inhibit protein kinase C (PKC). Recent studies indicate that some diphenylmethane derivatives inhibit growth, are potent AEBS ligands, and antagonize histamine binding at an AEBS-related histamine site different from H₁ and H₂. Three novel diphenylmethane derivatives, N,N-diethyl-2-[4-(phenylmethyl)phenoxyl]ethanamine·HCl (DPPE), 4-decanoyl-DPPE (dec-DPPE), and 4-benzylphenyl decanoate (BPD) were studied in an attempt to determine whether PKC or histamine interactions best correlate with their antiproliferative effects. Platelet aggregation and the phosphorylation of a platelet M_r 47,000 protein (p47) induced by phorbol-12-myristate-13-acetate (PMA) represent two processes mediated by PKC. DPPE inhibits PMA-induced aggregation [50% inhibitor concentration (IC₅₀) = 31.2 ± 2.4 (SEM) x 10^-6 M] but does not significantly inhibit either PMA-induced phosphorylation of M_r 47,000 protein (IC₅₀ > 500 x 10^-6 M), or binding of [³H]phorbol dibutyrate to platelets. dec-DPPE is a more potent inhibitor of PMA-induced platelet aggregation (IC₅₀ = 18.8 ± 0.7 x 10^-6 M), a weak inhibitor of M_r 47,000 phosphorylation (IC₅₀ = 80–200 x 10^-6 M), but is without effect on [³H] phorbol dibutyrate binding. BPD, which lacks the alkylaminoethoxy side chain necessary for binding to the AEBS/DPPE site, is devoid of anti-PMA effects. These results are compared to the inhibition of [³H]histamine binding in rat cortex membranes (K₁ value for DPPE = 0.83 ± 0.62 x 10^-6 M; K₁ value for dec-DPPE = 6.6 ± 3.5 x 10^-6 M; BPD is inactive) and growth inhibition of MCF-7 cells (IC₅₀ value for DPPE = 4.5 x 10^-6 M; IC₅₀ value for dec-DPPE = 1.5 x 10^-5 M; BPD is ineffective at all concentrations tested). Thus, while dec-DPPE is a more potent inhibitor of PKC-mediated phosphorylation, DPPE is a more potent inhibitor of histamine binding and is correspondingly more antiproliferative than dec-DPPE. The results support a relationship between antagonism of histamine binding and growth inhibition but argue against an association between the antiproliferative effects of DPPE and dec-DPPE and inhibition of PKC. The findings for DPPE suggest that platelet response to PMA, antagonized by diphenylmethane-type AEBS-ligands, may be mediated, at least in part, by mechanisms other than activation of protein kinase C-dependent phosphorylation.

¹ This work was supported by grants from the Manitoba Health Research Council, The University of Manitoba Faculty Fund, The Medical Research Council of Canada, and by a generous gift from the estate of Morris Katz.

² To whom requests for reprints should be addressed.

Received 1/25/88. Revised 4/ 7/88. Accepted 4/11/88.

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