Li Guang-xun, Lee Hyo-Jeong, Wang Zhe, Hu Hongbo, Liao Joshua D, Watts Jennifer C, Combs Gerald F, Lü Junxuan
Hormel Institute, University of Minnesota, 801 16th Avenue Northeast, Austin, MN 55912, USA.
Carcinogenesis. 2008 May;29(5):1005-12. doi: 10.1093/carcin/bgn007. Epub 2008 Feb 28.
Methylselenol has been implicated as an active anticancer selenium (Se) metabolite. However, its in vivo efficacy against prostate cancer (PCa) has yet to be established. Here, we evaluated the growth inhibitory effects of two presumed methylselenol precursors methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC) in comparison with selenomethionine (SeMet) and selenite in DU145 and PC-3 human PCa xenografts in athymic nude mice. Each Se was given by a daily single oral dose regimen starting the day after the subcutaneous inoculation of cancer cells. We analyzed serum, liver and tumor Se content to confirm supplementation status and apoptosis indices and tumor microvessel density for association with antitumor efficacy. Furthermore, we analyzed lymphocyte DNA integrity to detect genotoxic effect of Se treatments. The data show that MSeA and MSeC exerted a dose-dependent inhibition of DU145 xenograft growth and both were more potent than SeMet and selenite, in spite of less tumor Se retention than in the SeMet-treated mice. Selenite treatment increased DNA single-strand breaks in peripheral lymphocytes, whereas the other Se forms did not. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) and cleaved caspase-3 indices (apoptosis) from MSeC-treated tumors were higher than tumors from control mice or MSeA-treated mice, whereas the microvessel density index was lower in tumors from MSeA-treated mice. In the PC-3 xenograft model, only MSeA was growth inhibitory at a dose of 3 mg/kg body wt. In summary, our data demonstrated superior in vivo growth inhibitory efficacy of MSeA over SeMet and selenite, against two human PCa xenograft models without the genotoxic property of selenite.
甲基硒醇被认为是一种具有抗癌活性的硒（Se）代谢产物。然而，其对前列腺癌（PCa）的体内疗效尚未得到证实。在此，我们评估了两种假定的甲基硒醇前体甲基亚硒酸（MSeA）和硒甲基硒代半胱氨酸（MSeC）与硒代蛋氨酸（SeMet）和亚硒酸盐相比，对无胸腺裸鼠体内DU145和PC-3人PCa异种移植瘤的生长抑制作用。从皮下接种癌细胞后的第二天开始，每天通过单次口服给药的方式给予每种硒。我们分析了血清、肝脏和肿瘤中的硒含量，以确认补充状态，并分析了凋亡指数和肿瘤微血管密度与抗肿瘤疗效的关系。此外，我们分析了淋巴细胞DNA完整性，以检测硒处理的遗传毒性作用。数据表明，MSeA和MSeC对DU145异种移植瘤的生长具有剂量依赖性抑制作用，尽管它们在肿瘤中的硒保留量低于SeMet处理的小鼠，但二者均比SeMet和亚硒酸盐更有效。亚硒酸盐处理增加了外周淋巴细胞中的DNA单链断裂，而其他硒形式则没有。MSeC处理的肿瘤的末端脱氧核苷酸转移酶生物素-dUTP缺口末端标记（TUNEL）和裂解的半胱天冬酶-3指数（凋亡）高于对照小鼠或MSeA处理的小鼠的肿瘤，而MSeA处理的小鼠的肿瘤中的微血管密度指数较低。在PC-3异种移植模型中，只有剂量为3 mg/kg体重的MSeA具有生长抑制作用。总之，我们的数据表明，在两种人PCa异种移植模型中，MSeA对SeMet和亚硒酸盐具有优异的体内生长抑制效果，且没有亚硒酸盐的遗传毒性。
