Tipifarnib and tanespimycin show synergic proapoptotic activity in U937 cells

Abstract

Background: Farnesyltransferase inhibitor tipifarnib (R115777) has been used for treatment of hematological malignancies; however, its observed anticancer effect was limited. This prompted us to search for inhibitors that would show synergic, proapoptotic effect when combined with R115777.We decided to study LY294002,which inhibits PI-3 kinase, and tanespimycin (17AAG), which inhibits Hsp90-a chaperone for a number of proteins, including Akt kinase. Methods: The effect of drugs, used alone or in combination, was tested in U937 cells (human leukemic monocyte lymphoma), which are often used as a model for liquid tumor. The number of viable cells was evaluated with trypan blue staining, while apoptosis was assessed by presence of active caspase-3 and terminal dUTP nick-end labeling of DNA (TUNEL). Results: At concentrations in which R115777, LY294002 and 17AAG were only slowing down the proliferation rate, when used separately, the combination of R115777 + LY294002 and R115777 + 17AAG significantly reduced the number of cells and induced cellular apoptosis. Conclusions: Our results suggest that the combination of R115777 + 17AAG could be useful in treating some of the hematological malignancies. © The Author(s) 2011.