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 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.
Maeda
H
H
The 4th Department, Osaka Bioscience Institute, Osaka 565-0874, Japan.
Hori
S
S
Nishitoh
H
H
Ichijo
H
H
Ogawa
O
O
Kakehi
Y
Y
Kakizuka
A
A
D000728:Androgens / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases
D000728:Androgens; D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D017382:Reactive Oxygen Species; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020169:Caspases; D000077237:Arsenic Trioxide