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Sulforaphane Enhances the Therapeutic Potential of TRAIL in Prostate Cancer Orthotopic Model through Regulation of Apoptosis, Metastasis, and Angiogenesis

Authors' Affiliation: Department of Biochemistry, University of Texas Health Science Center at Tyler, Tyler, Texas

Requests for reprints: Rakesh K. Srivastava, Department of Biochemistry, University of Texas Health Science Center at Tyler,11937 U.S. Highway 271, Tyler, TX 75708-3154. Phone: 903-877-7559; Fax: 903-877-5320; E-mail: rakesh.srivastava{at}uthct.edu.

Purpose: The purpose of this study was to examine the molecular mechanisms by which sulforaphane enhances the therapeutic potential of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in prostate cancer.

Experimental Design: Cell viability and apoptosis assays were done by XTT and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, respectively. Tumor-bearing mice were treated with vehicle, sulforaphane, TRAIL, and sulforaphane plus TRAIL. Markers of apoptosis, angiogenesis, and metastasis were measured by immunohistochemistry.

Results: Sulforaphane enhanced the therapeutic potential of TRAIL in PC-3 cells and sensitized TRAIL-resistant LNCaP cells. Sulforaphane-induced apoptosis in PC-3 cells correlated with the generation of intracellular reactive oxygen species (ROS), collapse of mitochondrial membrane potential, activation of caspase-3 and caspase-9, and up-regulation of DR4 and DR5. Sulforaphane induced the expression of Bax, Bak, Bim, and Noxa and inhibited the expression of Bcl-2, Bcl-X_L, and Mcl-1. The quenching of ROS generation with antioxidant N-acetyl-L-cysteine conferred significant protection against sulforaphane-induced ROS generation, mitochondrial membrane potential disruption, caspase-3 activation, and apoptosis. Sulforaphane inhibited growth of orthotopically implanted PC-3 tumors by inducing apoptosis and inhibiting proliferation and also enhanced the antitumor activity of TRAIL. Sulforaphane up-regulated the expressions of TRAIL-R1/DR4, TRAIL-R2/DR5, Bax and Bak and inhibited the activation of nuclear factor-B P13K/AKT and MEK/ERK pathways in tumor tissues. The combination of sulforaphane and TRAIL was more effective in inhibiting markers of angiogenesis and metastasis and activating FOXO3a transcription factor than single agent alone.

Conclusions: The ability of sulforaphane to inhibit tumor growth, metastasis, and angiogenesis and to enhance the therapeutic potential of TRAIL suggests that sulforaphane alone or in combination with TRAIL can be used for the management of prostate cancer.

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