Terry Fox Cancer Research Lab, Graduate Institute of Chinese Medical Science, School of Medicine, China Medical University, Taichung, 404 Taiwan, ROC.
Anticancer Res. 2010 Sep;30(9):3655-60.
The anti-tumor properties of arsenic trioxide have attracted extensive attention after successfully inducing apoptosis of acute promyelocytic leukemia cells. However, the therapeutic spectrum should not only be restricted to acute promyelocytic leukemia, but should also extend into other types of tumor cells. In this study, we aimed at investigating its potential application to clinical therapeutics in oral cancer. In this preclinical animal test, primarily cultured cells from the tumor sites and normal sites of a two-drug (200 μg/ml 4-nitroquinoline 1-oxide (4NQO) plus 500 μg/ml arecoline)-induced oral cancer C57BL/6J Narl mice model were examined for their viabilities after treatments of arsenic trioxide with/without other drugs. In this model, the mice were treated with 4NQO plus arecoline (NA) in their drinking water for eight weeks (8-w), and the drugs were withdrawn for another 10 or 20 weeks (18-w and 28-w, respectively). The results showed that 2 μM of arsenic trioxide 24-h treatment suppressed the viabilities of cells primarily cultured from the tumor sites of 8-w, 18-w and 28-w NA-treated mice to 72.9%, 71.5% and 65.6%. However, it also suppressed the viabilities of cells from the sham-treated mice of 8-w, 18-w and 28-w to 76.8%, 73.4% and 75.7%, respectively. Therefore, 0.5 μM of arsenic trioxide treatment for 24 h, which suppressed the viabilities of cells primarily cultured from the tumor sites of 28-w NA-treated and sham-treated mice to 15.6% and 9.1%, was examined for its synergistic effects on the two primarily cultured cell lines with other drugs. The results showed that 10-20 μM dithiothreitol enhanced the cytotoxic effects of arsenic trioxide to 43.3~62.1%, better than those of 4 J/m(2) UVC, 20 μM H(2)O(2) or 100 μM buthionine sulfoximine (21.3%, 13.2%, and 14.2%, respectively). At the same time, 10-20 μM dithiothreitol plus 0.5 μM arsenic trioxide treatments caused only 12.3% and 15.2% of cell death in the control group. The cytotoxicity of dithiothreitol and arsenic trioxide combination on primarily cultured cells from this oral cancer model should be confirmed in human oral cancer cell lines before its application in clinical therapy, and the detailed mechanism is worth further investigation.
三氧化二砷的抗肿瘤特性在成功诱导急性早幼粒细胞白血病细胞凋亡后引起了广泛关注。然而，治疗范围不应仅限于急性早幼粒细胞白血病，还应扩展到其他类型的肿瘤细胞。在这项临床前动物试验中，我们旨在研究其在口腔癌临床治疗中的应用潜力。在该试验中，主要培养了两种药物（200μg/ml 4-硝基喹啉 1-氧化物（4NQO）加 500μg/ml 槟榔碱）诱导的口腔癌 C57BL/6J Narl 小鼠模型肿瘤部位和正常部位的细胞，并用三氧化二砷进行处理，并在有无其他药物的情况下检测细胞活力。在该模型中，用 4NQO 和槟榔碱（NA）处理小鼠饮用水 8 周（8w），然后停药 10 或 20 周（18w 和 28w）。结果表明，2μM 三氧化二砷处理 24 小时可将 8w、18w 和 28w 经 NA 处理的小鼠肿瘤部位原代培养细胞的活力抑制至 72.9%、71.5%和 65.6%。然而，它也将来自 8w、18w 和 28w 假处理小鼠的细胞活力抑制至 76.8%、73.4%和 75.7%。因此，检测了 0.5μM 三氧化二砷处理 24 小时对 28w 经 NA 处理和假处理小鼠肿瘤部位原代培养细胞的协同作用，该处理将细胞活力抑制至 15.6%和 9.1%。对两种原代细胞系与其他药物的协同作用进行了研究。结果表明，10-20μM 二硫苏糖醇增强了三氧化二砷的细胞毒性，达到 43.3%至 62.1%，优于 4J/m(2)UVC、20μM H(2)O(2)或 100μM 丁硫氨酸亚砜（分别为 21.3%、13.2%和 14.2%）。同时，在对照组中，10-20μM 二硫苏糖醇加 0.5μM 三氧化二砷处理仅导致 12.3%和 15.2%的细胞死亡。在将二硫苏糖醇和三氧化二砷联合应用于临床治疗之前，应在人口腔癌细胞系中进一步确认该口腔癌模型中原代培养细胞的细胞毒性，并值得进一步研究其详细机制。
