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Research Articles: Therapeutics, Targets, and Development

Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma

Departments of ¹ Medical Biophysics and ² Computer Science, University of Toronto; Divisions of ³ Cancer Genomics and Proteomics and ⁴ Signaling Biology, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada; and ⁵ Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona

Requests for reprints: Linda Z. Penn, Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9. Phone: 416-946-2276; Fax: 416-946-2840. E-mail: lpenn{at}uhnres.utoronto.ca

Abstract

Statins, commonly used to treat hypercholesterolemia, have been shown to trigger tumor-specific apoptosis in certain cancers, including multiple myeloma (MM), a plasma cell malignancy with poor prognosis. In this article, we show that of a panel of 17 genetically distinct MM cell lines, half were sensitive to statin-induced apoptosis and, despite pharmacodynamic evidence of drug uptake and activity, the remainder were insensitive. Sensitive cells were rescued from lovastatin-induced apoptosis by mevalonate, geranylgeranyl PPi, and partially by farnesyl PPi, highlighting the importance of isoprenylation. Expression profiling revealed that Rho GTPase mRNAs were differentially expressed upon lovastatin exposure in sensitive cells, yet ectopic expression of constitutively active Rho or Ras proteins was insufficient to alter sensitivity to lovastatin-induced apoptosis. This suggests that sensitivity involves more than one isoprenylated protein and that statins trigger apoptosis by blocking many signaling cascades, directly or indirectly deregulated by the oncogenic lesions of the tumor cell. Indeed, clustering on the basis of genetic abnormalities was shown to be significantly associated with sensitivity (P = 0.003). These results suggest that statins may be a useful molecular targeted therapy in the treatment of a subset of MM. [Mol Cancer Ther 2007;6(6):1886–97]

Grant support: Ontario Institute for Cancer Research Network through funding provided by the Province of Ontario (L.Z. Penn); an operating grant (L.Z. Penn), scholarship (W.W-L. Wong), and Excellence In Radiation Research for the 21st Century Strategic Training Initiative in Health Research awards (J.W. Clendening and P.C. Boutros) from the Canadian Institutes for Health Research; a scholarship from the National Science and Engineering Research Council (J.W. Clendening); a fellowship from Leukemia and Lymphoma Society of Canada (A. Martirosyan); a fellowship from Precarn (P.C. Boutros); and grants from IBM and the Institute for Robotics and Intelligent Systems (I. Jurisica).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: W.W-L. Wong and J.W. Clendening contributed equally to this work.

⁶ P.C. Boutros et al., in preparation.

⁷ http://www.stanford.edu/group/nolan/protocols/pro_optimiz.html

⁸ Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 12/ 4/06; revised 3/25/07; accepted 4/27/07.