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Mcl-1: A Gateway to TRAIL Sensitization

Laboratory of Molecular Oncology and Cell Cycle Regulation, Departments of Medicine (Hematology/Oncology), Genetics, Pharmacology, the Institute for Translational Medicine and Therapeutics and the Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Requests for reprints: Wafik S. El-Deiry, 415 Curie Boulevard, CRB 437, Philadelphia, PA 19104. Phone: 215-898-9015; Fax: 215-573-9139; E-mail: wafik{at}mail.med.upenn.edu.

Key Words: Mcl-1 • sorafenib • TRAIL

The proapoptotic cytokine tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is being evaluated presently as a selective anticancer agent, but its limited effects against cancer cell lines has raised some concerns about its ultimate clinical utility. Here, we review recent findings that cancer cell sensitivity to TRAIL is greatly increased when the Bcl-2 family protein Mcl-1 is down-regulated by the Raf/vascular endothelial growth factor kinase inhibitor sorafenib, a Food and Drug Administration–approved cancer drug. Using the TRAIL-sorafenib combination as a tactic to more effectively kill cancer cells may provide an effective tool to attack a variety of human cancers that are largely presently untreatable. [Cancer Res 2008;68(7):2062–4]