Department of Renal Medicine, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.
Nephrol Dial Transplant. 2010 May;25(5):1462-74. doi: 10.1093/ndt/gfp673. Epub 2009 Dec 27.
Renal cell carcinoma (RCC) is a highly metastatic and lethal disease with few efficacious treatments. Many studies have shown that the ubiquitous transcription factor nuclear factor kappa B (NF-kappaB) plays a key role in the development and progression of many cancers including RCC. The aim of this investigation was to evaluate the anti-cancer effect of pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor, in a murine xenograft model of RCC.
The metastatic human RCC cell line, SN12K1, was inoculated into the left kidneys of severe combined immunodeficiency mice and the effect of semi-continuous PDTC treatment (50 mg/kg) on RCC growth analysed 5 weeks later. The analyses carried out in three groups (no treatment, RCC alone and RCC + PDTC) at 5 weeks were: renal weight, protein expression by immunohistochemistry and Western immunoblot, apoptosis (TdT-mediated nick end labelling and morphology) and mitosis (morphology).
PDTC significantly decreased RCC growth and the expression of NF-kappaB subunits (p50, p52, c-Rel and RelB), upstream IKK-beta and IKK-gamma, but did not induce any changes in the expression of IkappaB-alpha and IkappaB-beta. RCC growth was associated with a significant decrease in the expression of the anti-apoptotic proteins Bcl-2 and Bcl-(XL) and increase in pro-apoptotic Bax, all of which were reversed by PDTC. Cell proliferation was significantly reduced by PDTC.
The results demonstrate the potential anti-cancer benefits of treating NF-kappaB positive RCCs with NF-kappaB inhibitors like PDTC.
肾细胞癌（RCC）是一种高度转移性和致命性疾病，治疗方法有限。许多研究表明，普遍存在的转录因子核因子 kappa B（NF-kappaB）在许多癌症的发展和进展中发挥着关键作用，包括 RCC。本研究旨在评估 NF-kappaB 抑制剂吡咯烷二硫代氨基甲酸盐（PDTC）在 RCC 小鼠异种移植模型中的抗癌作用。
将转移性人 RCC 细胞系 SN12K1 接种到严重联合免疫缺陷小鼠的左肾中，5 周后分析半连续 PDTC 治疗（50mg/kg）对 RCC 生长的影响。在 5 周时，在三组（无治疗、RCC 单独和 RCC+PDTC）中进行了以下分析：肾重、免疫组织化学和 Western 免疫印迹法的蛋白表达、细胞凋亡（TdT 介导的缺口末端标记和形态）和有丝分裂（形态）。
PDTC 显著降低了 RCC 的生长和 NF-kappaB 亚基（p50、p52、c-Rel 和 RelB）、上游 IKK-beta 和 IKK-gamma 的表达，但未诱导 IkappaB-alpha 和 IkappaB-beta 的表达发生任何变化。RCC 的生长与抗凋亡蛋白 Bcl-2 和 Bcl-（XL）的表达显著降低以及促凋亡 Bax 的表达增加有关，所有这些都被 PDTC 逆转。PDTC 显著降低了细胞增殖。
研究结果表明，用 NF-kappaB 抑制剂如 PDTC 治疗 NF-kappaB 阳性 RCC 具有潜在的抗癌益处。
