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The farnesyl transferase inhibitor, FTI-277, inhibits growth and induces apoptosis in drug-resistant myeloma tumor cells

Leukemia volume 17, pages 451–457 (2003)Cite this article

Abstract

Mutations of the ras gene are among the most commonly identified transforming events in human cancers, including multiple myeloma. Farnesyltransferase inhibitors (FTI) were developed to prevent Ras processing and induce cancer cell death. Several FTIs are in phase II and one is in phase III clinical trials. Preclinically, most of the focus has been on solid tumors, and the effects of FTIs in multiple myeloma have not been investigated. In this study we examined the cytotoxic activity and inhibition of Ras processing in three myeloma cell lines with differing Ras mutation status. H929 cells with activated N-Ras were more sensitive to FTI-277 treatment than 8226 and U266 cells with activated K-Ras or wild-type Ras, respectively. A combination of FTI-277 and a geranylgeranyltransferase I inhibitor (GGTI)-2166 inhibited K-Ras processing and enhanced cell death in 8226 cells. U266 cells and Bcl-xL transfectants were equally sensitive to FTI-277 treatment. Similarly, 8226 cells selected for resistance to various chemotherapeutic agents, which resulted in either P-glycoprotein overexpression, altered topoisomerase II activity, or elevated glutathione levels, were equally sensitive to FTI-277. These preclinical studies suggest that prenylation inhibitors may represent new therapeutic agents for the treatment of refractory or drug-resistant multiple myeloma.

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Acknowledgements

We thank the Flow Cytometry Core Facility at the H Lee Moffitt Cancer Center and Research Institute. This work was supported by NCI grants CA77859, CA82533, CA67771, CA76296 (H. Lee Moffitt Cancer Center Core Grant) CA21115 (ECOG) and the Peninsula Society for Myeloma Research.

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Authors and Affiliations

  1. Clinical Investigations, H Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, FL, USA

    S C E Bolick, T H Landowski, M M Oshiro & W S Dalton

  2. Drug Discovery Program, H Lee Moffitt Cancer Center, University of South Florida College of Medicine, Tampa, FL, USA

    S M Sebti

  3. Biostatistics Core, H Lee Moffitt Cancer Center, University of South Florida College of Medicine, Tampa, FL, USA

    D Boulware

  4. Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, FL, USA

    T H Landowski, M M Oshiro, S M Sebti & W S Dalton

  5. Department of Biochemistry and Molecular Biology, University of South Florida College of Medicine, Tampa, FL, USA

    S C E Bolick, S M Sebti & W S Dalton

  6. University of Arizona Cancer Center, Tucson, AZ, USA

    T H Landowski & M M Oshiro

  7. Department of Chemistry, Yale University, New Haven, CT, USA

    J Ohkanda & A D Hamilton

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  1. S C E Bolick
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Bolick, S., Landowski, T., Boulware, D. et al. The farnesyl transferase inhibitor, FTI-277, inhibits growth and induces apoptosis in drug-resistant myeloma tumor cells. Leukemia 17, 451–457 (2003). https://doi.org/10.1038/sj.leu.2402832

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  • DOI: https://doi.org/10.1038/sj.leu.2402832

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