Tumor growth inhibition by arsenic trioxide (As2O3) in the orthotopic metastasis model of androgen-independent prostate cancer

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 concent rations. In addition, the cell death mechanism of As2O3 has yet to be clari fied, especially in solid cancers, In this study, human androgen-independen t prostate cancer cell lines, PC-3, DU-145. and TSU-PR1 were examined as ce llular models for As2O3 treatment, and As2O3-induced cell death and inhibit ion of cell growth and colony formation were evaluated. The involvement of p38, c-Jun NH2-terminal kinase (JNK), caspase-3, and reactive oxygen specie s (ROS) were investigated in As2O3-induced cell death. Finally, As2O3 was a dministered to severe combined immunodeficient mire inoculated orthotopical ly with PC-3 tells to estimate in vivo efficacy. In all three of the cell l ines, at high concentrations, As2O3 induced apoptosis and, at low concentra tions, growth inhibition. As2O3 activated p38, JNK, and caspase-3 dose depe ndently. Treatment with the p38 inhibitor and over-expression of dominant-n egative JNK did not guard against As2O3-induced cell death, In contrast wit h partial protection by the caspase-3 inhibitor, the antioxidant N-acetyl-L -cysteine gave marked protection from As2O3-induced apoptosis and eliminate d 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 and rogen-independent prostate cancer. Generation of ROS as a therapeutic targe t for the potentiation of As2O3-induced apoptosis also was shown.