Albini A, D'Agostini F, Giunciuglio D, Paglieri I, Balansky R, De Flora S
Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
Int J Cancer. 1995 Mar 29;61(1):121-9. doi: 10.1002/ijc.2910610121.
The thiol N-acetylcysteine (NAC) 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 NAC. 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 NAC. 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.
硫醇N-乙酰半胱氨酸（NAC）因其影响化学致癌过程的多种协同机制，目前被认为是最有前景的癌症化学预防剂之一。最近的研究表明，前肽中未配对的半胱氨酸残基在潜伏性转移相关金属蛋白酶的失活中起关键作用：本研究旨在评估NAC是否也能影响恶性细胞的肿瘤形成、侵袭和转移。通过酶谱分析评估，NAC完全抑制了所测试细胞（明胶酶A和B）中IV型胶原酶的明胶溶解活性。此外，在预测侵袭和转移特性的Boyden小室试验中，NAC能有效抑制人源（A2058黑色素瘤）和鼠源（K1735和B16-F10黑色素瘤细胞以及C87刘易斯肺癌细胞）肿瘤细胞的趋化和侵袭活性。还原型谷胱甘肽（GSH）具有类似的活性，尽管效果较差。当将B16-F10鼠黑色素瘤细胞静脉注射到裸鼠体内并预先用NAC处理，然后重悬于补充有10 mM NAC的培养基中时，肺转移灶的数量急剧减少。在其他实验中，在皮下接种B16-F10细胞或其高转移变体B16-BL6之前48 - 72小时，或者在肌肉注射LLC细胞之前，通过饮用水给予NAC。在所有实验中，NAC处理均降低了局部形成的原发性肿瘤的重量，并产生了与剂量相关的肿瘤形成延迟。口服NAC可使B16-F10和B16-BL6肿瘤的自发转移形成略有但显著减少。然而，刘易斯肺癌肿瘤未观察到这种情况。这些数据表明，NAC可能通过其巯基抑制明胶酶来影响肿瘤细胞的侵袭和转移过程，其他机制可能也有贡献，包括该硫醇的强大抗氧化活性。
