Abstract 2061: Combination statin and chemotherapy treatment inhibits proliferation and cytotoxicity of an aggressive natural killer cell leukemia.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Aggressive natural killer cell leukemia is an acute neoplastic proliferation of natural killer cells, resulting in progressive disease and a poor prognosis. Establishing an effective treatment plan for aggressive natural killer cell leukemia has not been successful. Current clinical treatment plans rely on chemotherapeutic drug combinations; however, many patients do not respond well and often relapse or develop drug resistance leading to death within several months. Uncontrolled cell growth coupled to pathology caused by the natural killer cytotoxicity of the leukemia cells produces the mortality. New therapeutic approaches to this aggressive leukemia are needed. In recent years statin drugs, known for their cholesterol lowering ability, have been shown to have certain anti-tumor effects. In this study, the effect of combination chemotherapy and statin treatment on proliferation, cell cycle time and cytotoxicity was investigated using the aggressive natural killer cell line known at YT-INDY. In terms of anti-proliferative effect, combination treatment of YT-INDY with doxorubicin (1 nM and 0.1 nM) with 10 uM atorvastatin, fluvastatin or simvastatin resulted in significant (p<0.05) inhibition of tumor cell proliferation compared to either agent alone. Paclitaxel, at a concentration of 1 nM, in combination with 10 uM atorvastatin, fluvastatin or simvastatin resulted in significant (p<0.05) inhibition of proliferation. Lovastatin, when used with doxorubicin or paclitaxel provided no significant inhibition compared to controls. Atorvastatin (10 uM), in combination with teniposide (100 pM or 10 pM) or topotecan (1 nM or 100 pM), inhibited YT-INDY proliferation at a statistically significant level (p<0.05). Teniposide (1 nM) or topotecan (1 nM), in combination with fluvastatin (10 uM), provided significant (p<0.05) reduction of proliferation compared to any single agent. Consistent with the effects on proliferation, compared to untreated cells, statin alone or chemo alone controls, combination therapy with atorvastatin (10 uM) and doxorubicin, paclitaxel, teniposide or topotecan increased the cell cycle time of YT-INDY at nearly every chemo concentration tested. Finally, in addition to the anti-proliferative effect of chemotherapy and statin together, combination treatment with paclitaxel (10 nM) and fluvastatin (0.5 uM) or lovastatin (0.5 uM) resulted in significant (p<0.05) inhibition of natural killer cell cytotoxicity compared to any single agent. These results suggest that statins in combination with certain chemotherapeutic agents could provide a better anti-tumor response and improved patient outcomes, compared to chemotherapy alone, in those individuals with aggressive natural killer cell leukemias. Citation Format: Timothy A. Steele, Austin Henslee. Combination statin and chemotherapy treatment inhibits proliferation and cytotoxicity of an aggressive natural killer cell leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2061. doi:10.1158/1538-7445.AM2013-2061