Suppression of cell proliferation with induction of p21 by Cl(-) channel blockers in human leukemic cells.

The existence of Cl(-) channels in lymphocytes and neutrophils has been increasingly recognized, but the biological functions are not yet clear. We examined the effects of Cl(-) channel blockers on the cell proliferation and the cell cycle of human leukemic cell lines. The growth of leukemic cells was suppressed most efficiently by NPPB (5-nitro-2-(3-phenylpropylamino) benzoic acid), partially by 9-AC (9-anthracenecarboxylic acid) and tamoxifen, but not by stilbene compounds. NPPB increased the G0/G1 population and induced the expression of p21, one of the critical molecules for G1/S checkpoint. Antisense oligonucleotide for a NPPB-sensitive and stilbene-insensitive Cl(-) channel, ClC-2, sufficiently suppressed the ClC-2 protein synthesis, but did not affect the growth of leukemic cells. These findings suggest that NPPB-sensitive and stilbene-insensitive Cl(-) channels other than ClC-2 play important roles in cell cycles and cell proliferation of human leukemic cells.