Vaccine Research Institute of San Diego, San Diego Science Center, San Diego, California 92109, USA.
Prostate. 2013 Apr;73(5):489-99. doi: 10.1002/pros.22585. Epub 2012 Sep 19.
Hormonal ablation is the standard treatment for disseminated androgen-dependent prostate cancer. Although tumor growth is controlled at first, the tumor invariably recurs in the form of castration-resistant prostate cancer. This study assessed the efficacy of a new therapeutic strategy that combines plumbagin, a naturally occurring naphthoquinone, with androgen ablation.
Viewing microscopy chambers were placed in the dorsal skinfold of mice. Syngeneic prostate tissue was grafted within the chambers and allowed to vascularize. H2B-GFP/PTEN-P2 prostate cancer cells were co-implanted on top of the grafted prostate tissue. Androgen ablation was achieved using surgical castration. Intact and castrated mice were administered plumbagin or sham treatment. Tumor growth, mitosis and apoptosis were monitored in real-time using fluorescent Intra-Vital Microscopy. The mechanism of action of plumbagin was explored using human and mouse prostate cancer cells.
Whereas both plumbagin and castration alone impeded tumor growth, only the combination of plumbagin and castration caused profound tumor regression in vivo, mostly due to increased apoptosis of the tumor cells. The cytotoxicity of plumbagin was not affected by androgens in vitro, suggesting that microenvironmental factors not present in culture play a crucial role in the combination effect. Plumbagin-induced cell death was mediated, at least in part, by activation of ERK and was due to generation of reactive oxygen species, because it was abolished by the anti-oxidant N-acetyl-L-cysteine.
Androgen deprivation in combination with plumbagin may provide a significant improvement over androgen deprivation alone and deserves further evaluation.
激素消融是治疗扩散型雄激素依赖型前列腺癌的标准疗法。虽然肿瘤生长最初得到控制，但肿瘤总是以去势抵抗性前列腺癌的形式复发。本研究评估了一种新的治疗策略的疗效，该策略将天然萘醌化合物白花丹醌与雄激素消融相结合。
在小鼠背部皮肤褶皱处放置观察显微镜室。将同种前列腺组织移植到室内并使其血管化。将 H2B-GFP/PTEN-P2 前列腺癌细胞与移植的前列腺组织顶部共植入。通过手术去势实现雄激素消融。完整和去势的小鼠给予白花丹醌或假处理。使用荧光活体内显微镜实时监测肿瘤生长、有丝分裂和细胞凋亡。使用人和小鼠前列腺癌细胞探索白花丹醌的作用机制。
尽管白花丹醌和单独去势都能抑制肿瘤生长，但只有白花丹醌和去势的组合才能在体内引起肿瘤的显著消退，这主要是由于肿瘤细胞凋亡增加所致。白花丹醌的细胞毒性不受雄激素的影响，这表明培养中不存在的微环境因素在组合效应中起着至关重要的作用。白花丹醌诱导的细胞死亡至少部分是通过 ERK 的激活介导的，并且是由于活性氧的产生，因为抗氧化剂 N-乙酰-L-半胱氨酸可以消除它。
雄激素剥夺联合白花丹醌可能比单独雄激素剥夺有显著改善，值得进一步评估。
