PB0764 - Farnesyltransferase inhibitor tipifarnib regulates platelet function through thromboxane A2 generation

Background: Tipifarnib is a farnesyltransferase inhibitor that substantially protects against cardiovascular diseases and is currently undergoing clinical trials for the treatment of a variety of 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.

Aims: We investigated the functional role of tipifarnib and its molecular basis on the regulation of platelet activation.

Methods: We used washed murine platelets to evaluate the function of tipifarnib in platelet activation.

Results: We found that 2-MeSADP-induced secondary waves of aggregation and dense granule secretion were completely inhibited by tipifarnib while it did not have any effect on 2-MeSADP-induced primary aggregation. It is known that 2-MeSADP-induced secretion and the resultant secondary wave of aggregation are mediated by the positive feedback effect of thromboxane A2 (TxA2) generation, suggesting the important role of tipifarnib on TxA2 generation in platelets. Consistently, tipifarnib did not affect the dose-dependent 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 AKT and ERK phosphorylation only in non-aspirinated platelets but not in aspirinated platelets, indicating that tipifarnib regulates AKT and ERK phosphorylation mediated by TxA2 generation.

Conclusion(s): Tipifarnib plays a role in platelet function through the regulation of TxA2 generation, thereby indicating the possibility of using tipifarnib as a single key to treat a variety of cancer patients with thrombo-embolic complications in the future.