Farnesyl Transferase Inhibitors Enhance Death Receptor Signals and Induce Apoptosis in Multiple Myeloma Cells

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Abstract
Multiple myeloma is an incurable plasma cell malignancy in which Ras may be constitutively active either via interleukin-6 (IL-6) receptor signaling or by mutation. Inactivation of Ras may be achieved with farnesyl transferase (FTase) inhibitors a class of drugs which have shown promise in clinical trials particularly in patients with acute leukemia. This report investigates the efficacy of two distinct classes of FTase inhibitors in diverse myeloma cell lines and primary isolates. While Ras signaling has traditionally been linked to myeloma cell growth, we found that these compounds also potently triggered cell death. Death induced by perillic acid (PA) was caspase dependent without evidence of death receptor activation. Apoptosis was associated with mitochondrial membrane depolarization and activation of caspase-9 and 3 but proceeded despite over-expression of Bcl-X L a known correlate of relapsed and chemorefractory myeloma. In addition, Fas ligand and TRAIL mediated apoptosis was potentiated in death receptor resistant (U266) and sensitive (RPMI 8226/S) cell lines. Of clinical relevance, the FTase inhibitor R115777 induced cell death in myeloma lines at doses observed in clinical trials. Furthermore, both R115777 and PA induced cell death in primary isolates with relative specificity. Taken together these preclinical data provide evidence that FTase inhibitors may be an effective therapeutic modality for the treatment of multiple myeloma.