INHIBITION OF INVASION, GELATINASE ACTIVITY, TUMOR TAKE AND METASTASIS OF MALIGNANT-CELLS BY N-ACETYLCYSTEINE
INHIBITION OF INVASION, GELATINASE ACTIVITY, TUMOR TAKE AND METASTASIS OF MALIGNANT-CELLS BY N-ACETYLCYSTEINE
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DOI：
10.1002/ijc.2910610121
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发表时间：
1995-03-29
影响因子：
6.4
通讯作者：
DEFLORA, S
中科院分区：
文献类型：
--
作者：
ALBINI, A;DAGOSTINI, F;DEFLORA, S
巯基N-乙酰半胱氨酸（NAG）是目前公认的最有前途的癌症化学预防剂之一，它具有多种协同作用机制，影响化学致癌过程。最近的研究表明，前肽中的未配对半胱氨酸残基在潜在的转移相关金属蛋白酶的失活中起着关键作用：本研究旨在评估NAC是否也可以影响肿瘤的发生，侵袭和转移的恶性细胞。如通过酶谱分析所评估的，NAC完全抑制测试细胞中IV型胶原酶（明胶酶A和B）的明胶分解活性。此外，NAC在Boyden室测定中有效抑制人（A2058黑色素瘤）和鼠源肿瘤细胞（K1735和B16-F10黑色素瘤细胞以及C87刘易斯肺癌细胞）的趋化和侵袭活性，Boyden室测定可预测侵袭和转移特性。还原型谷胱甘肽（GSH）具有类似的活性，但有效性较低。当将B16-F10鼠黑色素瘤细胞静脉注射到裸鼠中，用NAC预处理并重悬于补充有10 mM NAG的培养基中时，肺转移的数量急剧减少。在其他实验中，在皮下接种B16-F10细胞或其高转移性变体B16-BL 6或肌内注射LLC细胞之前48-72小时开始，在饮用水中给予NAC。在所有实验中，NAC治疗降低了局部形成的原发性肿瘤的重量，并在肿瘤形成中产生了剂量相关的延迟。通过口服给予NAG，B16-F10和B16-BL 6肿瘤的自发转移形成轻微但显著减少。然而，这在刘易斯肺肿瘤中没有观察到。这些数据表明，NAC影响肿瘤细胞侵袭和转移的过程，可能是由于其巯基抑制明胶酶，与其他机制的可能贡献，包括有效的抗氧化活性的硫醇。(C)1995 Wiley-Liss，Inc.
The thiol N-acetylcysteine (NAG) is currently considered one of the most promising cancer chemopreventive agents by virtue of its multiple and coordinated mechanisms affecting the process of chemical carcinogenesis. Recent studies have shown that an unpaired cysteine residue in the propeptide plays a key role in inactivation of latent metastasis-associated metalloproteinases: the present study was designed to assess whether NAC could also affect tumor take, invasion and metastasis of malignant cells. As assessed by zymographic analysis, NAC completely inhibited the gelatinolytic activity of type-IV collagenases in the cells tested (gelatinases A and B). Moreover, NAC was efficient in inhibiting the chemotactic and invasive activities of tumor cells of human (A2058 melanoma) and murine origin (K1735 and B16-F10 melanoma cells as well as C87 Lewis lung carcinoma cells) in Boyden-chamber assays, which are predictive of the invasive and metastatic properties. Reduced glutathione (GSH) had a similar, although less effective activity. The number of lung metastases decreased sharply when B16-F10 murine melanoma cells, injected i.v. into nude mice, were pre-treated with NAC and resuspended in medium supplemented with 10 mM NAG. In other experiments NAC was given in drinking water, starting 48-72 hr before subcutaneous inoculation of either B16-F10 cells or of their highly metastatic variant B16-BL6, or intramuscular injection of LLC cells. In all experiments NAC treatment decreased the weight of the locally formed primary tumor and produced a dose-related delay in tumor formation. Spontaneous metastasis formation by B16-F10 and B16-BL6 tumors was slightly yet significantly reduced by oral administration of NAG. However, this was not observed for Lewis lung tumors. These data indicate that NAC affects the process of tumor-cell invasion and metastasis, probably due to inhibition of gelatinases by its sulfhydryl group, with the possible contribution of other mechanisms, including the potent antioxidant activity of this thiol. (C) 1995 Wiley-Liss, Inc.