Clinically relevant doses of statins were investigated for their in vitro inhibitory effects on proliferation, cell cycle progression, cytotoxicity, and ERK1 and ERK2 MAP kinase activation in the YT-INDY human natural killer cell leukemia. YT-INDY is a model for studying new therapies against natural killer cell leukemias. Statins interrupt the formation of cholesterol by inhibiting HMG-CoA reductase, which is responsible for controlling the rate of cholesterol synthesis. Distinct from their effects on LDL-cholesterol, statins have been shown to inhibit the growth and induced apoptosis of various leukemia cell lines. Compared to controls, a seven day incubation with 10 uM and 5 uM fluvastatin inhibited YT-INDY proliferation 24% and 13%, respectively. Under the same conditions, atorvastatin inhibited proliferation 21% and 9%, respectively. Mevalonate (1 mM) fully reversed the effects of the statins, indicating that the compounds were acting through inhibition of HMG-CoA reductase. When cell cycle analysis was performed, it was determined that, following seven days of incubation with 10 uM fluvastatin or atorvastatin, there was an increased percentage of cells in the G0/G1 phase and a reduction in the S and G2/M phases. While 5 uM statin concentrations showed a modest effect on cell cycle progression, the results were not statistically significant. These data indicated that the statins altered YT-INDY cell cycle progression, thus reducing cell proliferation. A two-day incubation of 5 uM fluvastatin or atorvastatin was sufficient to cause nearly complete abrogation of natural killer cell cytotoxicity, which could be reversed with 1 mM mevalonate or 10 uM geranylgeranyl pyrophosphate. This is significant because natural killer cell cytotoxicity is thought to produce the pulmonary damage seen in some natural killer cell leukemia patients. Since both proliferation and cytotoxicity are dependent upon the ERK MAP kinase signal transduction pathway, we investigated the effect of low dose statins on ERK1 and ERK2 activation. We showed that as little as 5 uM fluvastatin or atorvastatin significantly inhibited the activation of ERK1 and ERK2, which are constitutively expressed in YT-INDY. Finally, flow cytometric analysis of YT-INDY incubated for seven days with 5 uM or 10 uM fluvastatin or atorvastatin decreased the forward scatter and side scatter parameters. This indicated that YT-INDY cell size and granularity were reduced. From these investigations, we concluded that 1) clinically relevant concentrations of fluvastatin and atorvastatin inhibit the proliferation of YT-INDY, 2) inhibitory effects of the statins appear to be dependent on decreasing cell cycle progression, and 3) ERK1 and ERK2 MAP kinase activation is severely reduced. Given the typical poor prognosis for natural killer cell leukemia patients, these results may point the way to better therapeutic strategies for this devastating cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1564.