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¹ Department of Medicine, Division of Hematology and Oncology, ² Sylvester Cancer Center, and ³ Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL

Requests for Reprints:Mathias G. Lichtenheld, University of Miami School of Medicine, RMSB 3014, 1600 NW 10th Avenue, Miami, FL 33136. Phone: (305) 243-3301; Fax: (305) 243-4623. E-mail: mlichten{at}med.miami.edu

Ras activation is frequently observed in multiple myeloma either by mutation or through interleukin-6 receptor signaling. Recently, drugs designed to inhibit Ras have shown promise in preclinical myeloma models and in clinical trials. In this report, we characterize the pathways by which the clinically tested farnesyl transferase inhibitor (FTI) R115777 induces apoptosis in multiple myeloma cells. Contrary to the proposed mechanistic action of FTIs, we found that R115777 induces cell death despite Ras prenylation implying participation of Ras-independent mechanism(s). Apoptosis proceeded via an intrinsic cascade and was associated with an increase in the expression and activity of Bax. Bax activation correlated with a loss of mitochondrial membrane integrity and activation of the endoplasmic reticulum (ER) stress response. These pathways activate caspase-9 and consistent with this, cell death was prevented by caspase-9 blockade. Interestingly, cells overexpressing Bcl-X_L remained partially sensitive to R115777 despite suppression of mitochondrial membrane dysfunction and ER-related stress. Taken together, these results indicate that R115777 induces apoptosis in a Ras-independent fashion via multiple intrinsic pathways.

Key Words: Farnesyl transferase inhibitors • Ras • Myeloma • Apoptosis

Grant support:National Institute of Health Grants: K12 Miami AIDS Oncology Scientist Program CA77824-03 (D.M. Beaupre), R01 CA55811 (M.G. Lichtenheld), F31 GM20435 (E. Cepero); a Howard Hughes Medical Institute Fellowship (E.A. Obeng); a Senior Research Grant from the Multiple Myeloma Research Foundation (L.H. Boise); and an award from the The Woman's Cancer Association of the University of Miami (M.G. Lichtenheld).

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.

⁴ E. Cepero, A. M. King, and L. H. Boise. Caspase-9 and effector caspases have sequential and distinct effects on mitochondria, submitted for publication.

Received 9/18/03; revised 11/ 3/03; accepted 11/26/03.