Development of As203-besed new chemotherapy for advanced prostate cancer

三氧化二砷（As 203）在体内外诱导急性早幼粒细胞白血病患者的临床缓解和各种肿瘤细胞的凋亡。本研究的目的是开发以As 203为基础的治疗激素难治性前列腺癌和晚期肾癌的新化疗方案。本实验的主要结果如下：1）高浓度（10- 100 μ M）的As_（203）诱导细胞凋亡，低浓度（0.1 μ M）的As_（203）诱导细胞凋亡。10 μ M）的As 2 O3导致雄激素不敏感的前列腺癌PC 3和Du 145细胞的细胞生长抑制。2）As 203呈剂量依赖性激活p38、JNK、caspase-3。3）抗氧化剂N-乙酰半胱氨酸通过抑制p38、JNK和caspase-3的活性及ROS的产生来抑制As 203诱导的细胞凋亡。基于上述结果，我们研究了低浓度的As 203是否可以通过抑制自由基清除系统诱导细胞凋亡。因此，较低浓度的As 2 O3与L-丁硫氨酸亚砜亚胺（BSD）的组合在体外成功地诱导了前列腺癌、肾癌、乳腺癌和肺癌中的细胞凋亡，但在正常细胞中没有诱导细胞凋亡（Cell Death Differ 2004）。

Arsenic trioxide (As203) induces clinical remission in acute promyelocytic leukemic patients and apoptosis in various tumor cells in vitro and in vivo. The purpose of this study is to develop As203-based new chemotherapy for hormone refractory prostate cancer and advanced renal cancer. Major findings of our experiments are following ; 1)Higher concentration (10-100uM) of As203 induced apoptosis and lower concentration 0.1? 10uM) of As203 resulted in inhibition of cell growth in androgen insensitive prostate cancer PC3 and Du145 cells. 2)As203 activated p38, JNK, caspase-3 in a dose-dependent manner. 3)An anti-oxidant N-acetyl-cysteine inhibited the apoptosis induced by As203 through suppressing p38, JNK, and caspase-3 activity and ROS production. Based on the results described above, we investigated whether lower concentration of As203 could induce apoptosis by suppressing radical scavenging system. As a consequence, combination of lower concentration of As203 with L-buthionine sulfoximine (BSD) successfully induced apoptosis in prostate, renal, breast, and lung cancers in vitro but did not in normal cells (Cell Death Differ 2004).