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¹ VA Greater Los Angeles Healthcare System and ² School of Medicine, University of California at Los Angeles, Los Angeles, California

Requests for reprints: Matthew B. Rettig, VA Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Building 304, Room E1-113, Los Angeles, CA 90073. Phone: 310-478-3711, ext. 44761; Fax: 310-268-4508. E-mail: matthew.rettig{at}med.va.gov

Advanced renal cell carcinoma (RCC) is resistant to cytotoxic chemotherapy, and immunotherapy has modest activity. Proteasome inhibitors represent a novel class of anticancer agents that have activity across a wide spectrum of tumor types. We investigated the efficacy of the proteasome inhibitor bortezomib (VELCADE, formerly known as PS-341) in RCC and found that bortezomib potently induces apoptosis of RCC cell lines. Blockade of the nuclear factor-B (NF-B) pathway is considered a crucial effect in bortezomib-induced apoptosis, but the dependence on NF-B inhibition for bortezomib-mediated death has not been formally demonstrated. Thus, we also studied the contribution of NF-B inhibition as a mechanism of bortezomib-induced apoptosis in RCC cells, which display constitutive NF-B activation. Ectopic expression of the NF-B family members, p65 (Rel A) and p50 (NF-B1), markedly reduced bortezomib-induced apoptosis. However, when we used selective genetic and chemical inhibitors of NF-B, we found that NF-B blockade was not sufficient to induce apoptosis of RCC cells. Thus, we conclude that maximal bortezomib-induced apoptosis is dependent on its NF-B inhibitory effect, but NF-B-independent effects also play a critical role in the induction of apoptosis by bortezomib. This represents the first report to formally demonstrate that bortezomib-induced NF-B blockade is required to achieve the maximum degree of apoptosis by this drug.

Received 11/ 6/03; revised 4/ 6/04; accepted 4/13/04.