Arsenic trioxide induces apoptosis in uveal melanoma cells through the mitochondrial pathway.
Uveal melanoma, the most common primary intraocular malignancy in adults, is highly resistant to most chemotherapeutic drugs. Arsenic trioxide (ATO) is known to inhibit ocular melanoma cell growth. However, the effects of ATO on human uveal melanoma cells are poorly understood. Therefore, this study evaluated the mechanisms of ATO and its inhibiting effects on a human uveal melanoma cell line (SP6.5). An MTT assay indicated that, compared to human fibroblasts, ATO had a stronger inhibiting effect on SP6.5 cell proliferation in a dose- and time-dependent manner. The apoptosis ratio in SP6.5 cells, which was indicated by cell DNA fragmentation, was 4.1- to 7.7-fold higher after ATO-treatment. The ATO treatment substantially increased the activities of caspase-3 and caspase-9, but not of caspase-8. These findings were consistent with the protein expression observed by Western blots. ATO also significantly enhanced expression of Bax and cytochrome c proteins but suppressed those of Bcl-2. Therefore, ATO-induced apoptosis in uveal melanoma cells occurs mainly through the mitochondrial pathway rather than through the death receptor pathway. This report is the first to evaluate the complete mitochondria-dependent apoptotic pathway of ATO in uveal melanoma cells. These results can be used to improve the clinical effectiveness of ATO treatment for uveal melanoma.
Department of Medical Research, Show Chwan Memorial Hospital, Changhua, Taiwan.
Miao-Ju
MJ
Chen
Pei-Yu
PY
Yang
Yi-Zhen
YZ
Ye
Dan-Ning
DN
Hu
Ming-Feng
MF
Chen
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology* / Q000627:therapeutic use; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D005134:Eye Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D008517:Phytotherapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9; D000077237:Arsenic Trioxide