Tim Steele, Ph.D., MT (ASCP)

Aggressive natural killer cell leukemia is an acute, rapid neoplastic proliferation of natural killer cells, resulting in a progressive disease and rapid mortality. Unfortunately, establishing an effective standard treatment plan for aggressive natural killer cell leukemia has been met with limited success. Current clinical treatment plans rely on several chemotherapeutic drug combinations; however, many patients do not respond well and often relapse or develop drug resistance. A patient’s prognosis is usually measured in weeks to months. Clearly, an advance in treatment strategy is necessary to improve patient prognosis.

Typically, statins are utilized to lower cholesterol by inhibiting the production of mevalonate via competitive inhibition of HMG-CoA reductase. Statins have also been shown to exhibit anti-cancer effects. Research in our lab has shown combination therapy with a chemotherapy agent and statin decreased cell proliferation and cytotoxicity of an aggressive natural killer cell leukemia cell line (YT-INDY).

Results to date include the following:

• Statin drugs alone inhibited YT-INDY proliferation, cytotoxicity and ERK MAP kinase phosphorylation.
• The combination of statin drugs and certain chemotherapeutic agents resulted in a time and dose-dependent inhibition of YT-INDY proliferation.
• The lipophilic statins (atorvastatin, fluvastatin, or simvastatin) in combination with doxorubicin, paclitaxel, teniposide or topotecan yielded better inhibitory effects on YT-INDY proliferation than either drug alone.
• The combination of the statins with paclitaxel and topotecan resulted in an enhanced inhibition of YT-INDY cytotoxicity compared to either drug alone.
• Geranylgeranyl transferase inhibitor (GGTI-286) and tipifarnib, both inhibitors of the mevalonate pathway inhibited YT-INDY proliferation, indicating that farnesylation and geranylgeranylation processes were important in YT-INDY proliferation.
• The addition of geranylgeranyl pyrophosphate to fluvastatin-treated YT-INDY cells restored proliferation, whereas the addition of farnesyl pyrophosphate showed a modest increase in restoration of growth, but did not restore growth to a statistically significant level.
• Fluvastatin altered the phosphorylation level of multiple proteins in the MAP kinase pathways that play a role in the control of proliferation and apoptosis.

Publications

Crosbie J., Magnussen M., Dornbier R., Iannone A., Steele, T.A. (2013) Statins Inhibit Proliferation and Cytotoxicity of a Human Leukemic Natural Killer Cell Line. Biomarker Res. 1: 33-40.

Steele, T.A. and Hauser, C.C. Role of Interferon-α in a successful murine tumor therapy. Exp. Biol. Med. 230: 487-493., 2005

Young H.E., Duplaa C., Yost M.J., Henson N.L., Floyd J.A., Detmer K., Thompson A.J., Powell S.W., Gamblin T.C., Kizziah K., Holland B.J., Boev A., Van De Water J.M., Godbee D.C., Jackson S., Rimando M., Edwards C.R., Wu E., Cawley C., Edwards P.D., Macgregor A., Bozof R., Thompson T.M., Petro G.J. Jr, Shelton H.M., McCampbell B.L., Mills J.C., Flynt F.L., Steele T.A., et al. Clonogenic analysis reveals reserve stem cells in postnatal mammals. II. Pluripotent epiblastic-like stem cells. Anatomical Record 277A: 178-203., 2004

Young H.E., Duplaa C., Romero-Ramos M., Chesselet M.F., Vourc’h P., Yost M.J., Ericson K., Terracio L., Asahara T., Masuda H., Tamura-Ninomiya S., Detmer K., Bray R.A., Steele T.A., et al. Adult reserve pluripotent stem cells and their potential for tissue engineering. Cell Biochem. Biophys. 40: 1-80., 2004

Shackelford, R.E., Mansuszak, R.P., Johnson, C.D., Hellrung, D.J., Steele, T.A., Link, C.J., and Wang, S. Desferrioxamine treatment increases the genomic stability of Ataxia-telangiectasia cells. DNA Repair 2: 971-981., 2003

Steele, T.A. Clinical significance of interleukin-18. Leuk. Res. 26: 975-976., 2002

Steele, T.A. Clinical significance of interleukin-18. Leuk. Res. 26: 975-976., 2002

Steele, T.A. Chemotherapy-induced immunosuppression and reconstitution of immune function. Leuk. Res. 26: 107-110., 2002

Mawson, T. and Steele, T.A. Possible role of retinoids in hepatitis B virus-associated liver damage. Exp. Biol. Med. 226: 734-739., 2001

Young, H.E., Steele, T.A., Bray, R.A., Hudson, J., Floyd, J.A., Hawkins, K., Thomas, K., Austin, T., Edwards, C., Cuzzourt, J., Duenzl, M., Lucas, P.A. and Black, Jr., A.C. Human reserve pluripotent mesenchymal stem cells are present in the connective tissues of skeletal muscle and dermis from fetal, adult, and geriatric donors. Anat. Record 264: 51-62., 2001

Steele, T.A. and Carpenter, S.S. Immunotherapeutic strategies for ovarian cancer. Mod. Asp. Immunobiol. 1: 131-135., 2000

K. Detmer, A.N. Walker, T.M. Jenkins, T.A. Steele and H. Dannawi. Erythroid differentiation in vitro is blocked by cyclopamine, an inhibitor of Hedgehog signaling. Blood Cells, Molecules, and Diseases. Blood Cells Mol. Dis. 26: 360-372., 2000

Steele, T.A. Recent developments in the virus therapy of cancer. Proc. Soc. Exp. Biol. Med. 223: 118-127., 2000

Detmer, K., Steele, T.A., Shoop, M., Dannawi, H. Lineage-restricted expression of the bone morphogenetic protein-7 and placental bone morphogenetic protein genes in human hematopoietic cell lines. Blood Cells Mol. Dis. 25: 310-323., 1999

Young, H. E., Steele, T.A., Bray, R. A., Detmer, K., Blake, L. W., Lucas, P. A., and Black, Jr, A. C. Human pluripotent and progenitor cells display cell surface cluster differentiation markers CD10, CD13, CD56 and MHC class-I. Proc. Soc. Exp. Biol. Med. 221: 63-71., 1999

Steele, T.A. and Cox, D. C. Elimination of EL-4 and L1210 murine tumors by 1,3-bis (2-chloroethyl)-1-nitrosourea requires an intact immune response. Proc. Soc. Exper. Biol. Med. 212: 63-68., 1996

Al-Sheboul, S., Crosely, D. and Steele, T.A. Inhibition of reovirus-stimulated murine natural killer cell cytotoxicity by cyclosporine. Life Sci. 59: 1675-1682., 1996

Steele, T.A. and Cox, D. C Reovirus type 3 chemoimmunotherapy of murine lymphoma is abrogated by cyclosporine. Cancer Biother. 10: 307-315., 1995

Steele, T.A. and Brahmi, Z. Phosphatidylinositol metabolism in tumor target cell-stimulated human natural killer cells. In: Natural Killer Cells and Host Defense (E. W. Ades and C. Lopez, ed.) p. 167-171. S. Karger Publishers, Inc., New York., 1989

Steele, T.A. and Brahmi, Z. Inhibition of human natural killer cell activity by the protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) is an early but postbinding event. J. Immunol. 141: 3164-3169., 1988

Steele, T.A. and Brahmi, Z. Phosphatidylinositol metabolism accompanies early activation events in tumor target cell-stimulated human natural killer cells. Cell. Immunol. 112: 402-413., 1988

Steele, T.A. and Brahmi, Z. Chlorpromazine inhibits human natural killer cell activity and antibody-dependent cell-mediated cytotoxicity. Biochem. Biophys. Res. Comm. 155: 597-602., 1988