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Tumor Growth Inhibition by Arsenic Trioxide (As₂O₃) in the Orthotopic Metastasis Model of Androgen-independent Prostate Cancer¹

The 4th Department, Osaka Bioscience Institute, Osaka 565-0874 [H. M., S. H., A. K.]; Department of Urology, Faculty of Medicine, Kyoto University, Kyoto 606-8507 [H. M., Y. K., O. O.]; Department of Biomaterials Science, Faculty of Dentistry, Tokyo Medical and Dental University, Tokyo 113-8549 [H. N., H. I.]; and CREST, JST (Japan Science and Technology Corporation), Kawaguchi City, Saitama Prefecture 332-0012 [A. K.], Japan

Arsenic trioxide (As₂O₃) induces clinical remission of patients with acute promyelocytic leukemia. As a novel anticancer agent for treatment of solid cancers, As₂O₃ is promising, but no in vivo experimental investigations of its efficacy on solid cancers have been done at clinically obtained concentrations. In addition, the cell death mechanism of As₂O₃ has yet to be clarified, especially in solid cancers. In this study, human androgen-independent prostate cancer cell lines, PC-3, DU-145, and TSU-PR1 were examined as cellular models for As₂O₃ treatment, and As₂O₃-induced cell death and inhibition of cell growth and colony formation were evaluated. The involvement of p38, c-Jun NH₂-terminal kinase (JNK), caspase-3, and reactive oxygen species (ROS) were investigated in As₂O₃-induced cell death. Finally, As₂O₃ was administered to severe combined immunodeficient mice inoculated orthotopically with PC-3 cells to estimate in vivo efficacy. In all three of the cell lines, at high concentrations, As₂O₃ induced apoptosis and, at low concentrations, growth inhibition. As₂O₃ activated p38, JNK, and caspase-3 dose dependently. Treatment with the p38 inhibitor and over-expression of dominant-negative JNK did not guard against As₂O₃-induced cell death. In contrast with partial protection by the caspase-3 inhibitor, the antioxidant N-acetyl-L-cysteine gave marked protection from As₂O₃-induced apoptosis and eliminated the activation of p38, JNK, and caspase-3, and the generation of ROS. The orthotopic murine metastasis model showed in vivo tumor growth inhibition in orthotopic and metastatic lesions with no signs of toxicity. This study establishes that As₂O₃ provides a novel, safe approach for treatment of androgen-independent prostate cancer. Generation of ROS as a therapeutic target for the potentiation of As₂O₃-induced apoptosis also was shown.

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