The antitumor agent tamoxifen inhibits breakdown of polyphosphoinositides in GH4C1 cells.

Tamoxifen, an antibreast cancer agent, is mainly known as an antiestrogenic drug. However, recently, it was shown that tamoxifen also has antiproliferative effects that are estrogen independent. The author showed that tamoxifen causes stimulation of phosphatidylinositol kinase and phosphatidylinositol-4-phosphate kinase activities. These enzymes are normally product inhibited by the polyphosphoinositides. Tamoxifen binds to the polyphosphoinositides, which thereby releases the kinases from product inhibition. The author now shows that binding of tamoxifen to the polyphosphoinositides also leads to inhibition of phospholipase C (PLC) activity. Tamoxifen caused the inhibition of inositol phosphate accumulation, which was stimulated in whole GH4C1 cells in culture by either thyrotropin-releasing hormone or bombesin. This drug also inhibited phosphoinositide breakdown in GH4C1 membrane preparations stimulated by guanosine-5'-O-(3-thiotriphosphate) or by 1 mM Ca++ and in an in vitro system in which PLC was measured with an enzyme preparation solubilized from GH4C1 membranes and exogenous substrate. All other enzymes of the phosphoinositide breakdown cascade were not inhibited by this drug. In light of the increasing evidence for the involvement of PLC activity in cell proliferation, it was suggested that at least part of the estrogen-independent anticancer properties of tamoxifen might be related to the blocking of phosphoinositide breakdown by the drug.