Parsons P G, Favier D, McEwan M, Takahashi H, Jimbow K, Ito S
Queensland Institute of Medical Research, Brisbane, Australia.
Melanoma Res. 1991 Jun-Jul;1(2):97-104. doi: 10.1097/00008390-199106000-00004.
Systemically administered 4-S-cysteaminylphenol (4-S-CAP) and N-acetyl-4-S-CAP inhibited the growth of xenografts of a human melanoma cell line but not of an ovarian tumour cell line. No selective cytotoxicity for melanoma cells was observed in culture, however. Further study of the in vitro mechanism of 4-S-CAP toxicity showed minimal inhibition of tyrosinase activity or DNA, RNA and protein synthesis, and there was no phase-specific arrest of the cell cycle. However, expression of an 80 kD melanosomal antigen was decreased. Cytotoxicity of 4-S-CAP in culture was decreased by simultaneous treatment with a monoamine oxidase inhibitor. An affinity column prepared from 4-S-CAP retained several proteins from a melanoma cell lysate. One protein, found also in HeLa cells, was identified by N-terminal sequencing as protein disulphide isomerase, a molecule which has multiple roles in the modification of secretory proteins. These results identify a protein target for 4-S-CAP as one possible mechanism of cytotoxicity.
全身给药的4-S-半胱氨酰苯酚（4-S-CAP）和N-乙酰-4-S-CAP可抑制人黑色素瘤细胞系异种移植物的生长，但对卵巢肿瘤细胞系无效。然而，在培养中未观察到对黑色素瘤细胞的选择性细胞毒性。对4-S-CAP毒性体外机制的进一步研究表明，酪氨酸酶活性或DNA、RNA和蛋白质合成的抑制作用极小，且细胞周期无阶段特异性停滞。然而，80 kD黑素体抗原的表达降低。同时用单胺氧化酶抑制剂处理可降低4-S-CAP在培养中的细胞毒性。由4-S-CAP制备的亲和柱保留了黑色素瘤细胞裂解物中的几种蛋白质。通过N端测序鉴定出一种也存在于HeLa细胞中的蛋白质为蛋白质二硫键异构酶，该分子在分泌蛋白修饰中具有多种作用。这些结果确定了4-S-CAP的一个蛋白质靶点，这可能是其细胞毒性的一种机制。
