Inhibition of Aggressive Natural Killer Cell Leukemia Cell Functions by Inhibitors of the Mevalonate Pathway and Its Products

Abstract

Aggressive natural killer cell leukemia is a rare form of leukemia characterized by an increase in proliferation of malignant natural killer cells. Aggressive natural killer cell leukemia is one of the deadliest cancers known. Survival time is normally weeks to a few months once diagnosed. Aggressive natural killer cell leukemia is highly resistant to treatment, making it important to find a treatment for natural killer cell leukemia. In this study, effects of a geranylgeranyl transferase inhibitor, a farnesyl transferase inhibitor, and Rho GTPase inhibitors were investigated on the aggressive natural killer cell line YT‐INDY. Cancer cells are capable of upregulating mevalonate metabolism for protein prenylation and cholesterol biosynthesis. The farnesyl transferase inhibitor Tipifarnib and geranylgeranyl transferase inhibitor GGTI‐286 inhibit mevalonate metabolism by blocking the farnesylation and geranylgeranylation of proteins, respectively. We investigated the effects of GGTI‐286 and Tipifarnib on cell proliferation, cell cycle progression, and activation of the ERK MAP kinase pathway. Rho GTPases are small molecules that, when active, regulate functions such as progression through the cell cycle, cell growth, and transcription. Upregulation of Rho GTPases have been found in certain cancers. We determined whether the Rac1 inhibitors NSC 23766 and EHT 1864, cdc42 inhibitors ZCL 278 and ML 141 and ROCK inhibitors GSK429286A and Y‐27632 could inhibit YT‐INDY cell proliferation and ERK MAP kinase activation. The results of our investigations showed that Tipifarnib and GGTI‐286 were potent inhibitors of YT‐INDY proliferation (Tipifarnib IC50 = 7.2 uM, and GGTI‐286 IC50 = 8.0 uM), cell cycle progression and ERK MAP kinase activation. Among the Rho GTPase inhibitors, we found that the ROCK inhibitors (GSK429286A and Y‐27632) and Rac1 inhibitors (NSC 23766 and EHT 1864) produced significant inhibition of YT‐INDY proliferation. We concluded from these investigations that inhibitors of the mevalonate pathway or products of the mevalonate pathway can interrupt YT‐INDY cell growth, suggesting that this approach could lead to more effective treatment of this devastating cancer.Support or Funding InformationOur laboratory gratefully acknowledges the financial support of this research by the Iowa Osteopathic Education and Research Foundation.