Effects and molecular mechanisms of farnesyltransferase inhibitor tipifarnib on platelet activation.

Abstract

Tipifarnib, a farnesyltransferase inhibitor, substantially protects against cardiovascular diseases and is currently undergoing clinical trials to treat various cancers. Platelets have a well-recognized role in the progression of cancer-associated cardiovascular diseases. Nevertheless, the effect of tipifarnib on platelet function has not been studied thus far. Thus, we investigated the effect of tipifarnib and its molecular basis on the regulation of platelet activation. 2-Methylthioadenosine diphosphate (2-MeSADP)-induced secondary waves of aggregation and dense granule secretion in murine-washed platelets were completely inhibited by tipifarnib. Since 2-MeSADP-induced secretion and the resultant secondary wave of aggregation are mediated by the positive feedback effect of thromboxane A₂ (TxA₂) generation, it suggests the important role of tipifarnib on TxA₂ generation in platelets. Consistently, tipifarnib did not affect the 2-MeSADP-induced platelet aggregation in aspirinated platelets where the contribution of TxA₂ generation was blocked. In addition, platelet aggregation and secretion induced by low concentrations of AYPGKF and thrombin, which are affected by the positive feedback effect of TxA₂ generation, were partially inhibited by tipifarnib. Importantly, the ELISA assay showed that 2-MeSADP- and AYPGKF-induced TxA₂ generation was significantly inhibited in the presence of tipifarnib, confirming the role of tipifarnib on TxA₂ generation. Finally, tipifarnib significantly inhibited 2-MeSADP-induced protein kinase B and extracellular signal-regulated kinases phosphorylation only in nonaspirinated platelets but not in aspirinated platelets, indicating the contribution of TxA₂ generation. Tipifarnib plays a role in platelet function by regulating TxA₂ generation, thereby indicating the possibility of using tipifarnib as a single key to treat various patients with cancer with thromboembolic complications in the future. SIGNIFICANCE STATEMENT: Farnesyltransferase inhibitor tipifarnib regulates platelet activity by inhibiting thromboxane A₂ generation through the modulation of protein kinase B and extracellular signal-regulated kinase phosphorylation. Given the dual role of platelets in both thrombosis and cancer progression, tipifarnib's ability to modulate these pathways highlights its potential as a therapeutic agent in preventing thromboembolic complications in patients with cancer.