INHIBITION OF PROTEIN TYROSINE PHOSPHATASE BY THE ANTITUMOR AGENT GALLIUM NITRATE

Protein tyrosine phosphatases (PTPases) play an important role in regu lating cell growth and transformation. We report that the antitumor ag ent gallium nitrate is a potent inhibitor (concentration producing 50% inhibition, 2-6 muM) of detergent-solubilized cellular membrane PTPas e from Jurkat human T-cell leukemia cells and HT-29 human colon cancer cells. This is the first report of a selective, small molecule drug i nhibitor of PTPase. Gallium nitrate did not inhibit CD45, a PTPase fou nd in the membranes of hemopoietic lineage cells such as Jurkat cells. Studies with gallium nitrate and a series of gallium-containing analo gues revealed no correlation between growth-inhibitory activity in Jur kat and HT-29 cells and the ability to inhibit detergent-solubilized P TPase. Gallium nitrate and most of the gallium analogues penetrate poo rly into cells. In contrast, a gallium-hydrogen peroxide complex inhib its DNA synthesis in Jurkat cells and induces the accumulation of phos photyrosines on multiple intracellular proteins in this cell line. Gal lium-hydrogen peroxide complex and gallium nitrate have similar inhibi tory activity toward detergent-soluble PTPase. This is a new mechanism of action for gallium nitrate but it is not known if the inhibition o f PTPase is related to the antitumor activity of gallium nitrate.