Development of As203-besed new chemotherapy for advanced prostate cancer

三氧化二砷(As203)在体内外均能诱导急性早幼粒细胞白血病患者的临床缓解和多种肿瘤细胞的凋亡。本研究的目的是开发基于As203的激素难治性前列腺癌和晚期肾癌的新化疗方案。本实验的主要研究结果如下：1)高浓度(10~100uM)的As203和较低浓度(0.1~10uM)的As203对雄激素不敏感的前列腺癌PC3和Du145细胞的生长均有抑制作用。2)As203对p38、JNK、caspase-3的激活呈剂量依赖性。3)抗氧化剂N-乙酰半胱氨酸通过抑制p38、JNK、caspase-3的活性和ROS的产生，抑制As203诱导的细胞凋亡。基于上述结果，我们研究了较低浓度的As203是否通过抑制自由基清除系统而诱导细胞凋亡。因此，较低浓度的As203与L-丁硫氨酸亚磺胺(BSD)在体外成功地诱导了前列腺癌、肾癌、乳腺癌和肺癌的凋亡，但对正常细胞却没有诱导凋亡(细胞死亡不同于2004年)。

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).