Inhibitors of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced multinucleated cell formation and HTLV-I p19 antigen expression in HTLV-I-infected T-cell line KH-2Lo.

To elucidate the biological mechanisms of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced phenotypic changes in HTLV-I virus-infected human T-cell line KH-2Lo cells, inhibitors of TPA-induced ornithine decarboxylase (ODC), protein kinases and calmodulin were examined for their effects on TPA-induced multinucleated cell formation and HTLV-I p19 antigen expression. Among the inhibitors of TPA-induced ODC activity, alpha-difluoromethyl ornithine (DFMO), 1,25(OH)2D3 and its analogues, and retinoic acid were tested. As inhibitors of protein kinases, 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7), N-[2-(methylamino)ethyl]-5-isoquinoline-sulfonamide (H-8) and 1,(5-isoquinolynylsulfonyl)-2,3-dimethylpiperazine (H-5) were used. In addition, a calmodulin inhibitor, N-(4-aminobutyl)-5-chlor-2-naphthalenesulfonamide (W13) and its inactive analogue, N-(4-aminobutyl)-2-naphthalenesulfonamide (W12) were also tested. 1,25(OH)2D3 and its active analogues inhibited both TPA-induced HTLV-I p19 antigen expression and multinucleated cell formation after 4 days of culture with TPA. On the other hand, an inhibitor of ODC, DFMO, the protein kinase inhibitors, the calmodulin inhibitor and retinoic acid suppressed TPA-induced HTLV-I p19 expression but did not suppress multinucleated cell formation.