State Key Laboratory of Applied Organic Chemistry , Lanzhou University , 222 Tianshui Street South , Lanzhou , Gansu 730000 , People's Republic of China.
J Agric Food Chem. 2019 Aug 14;67(32):9060-9069. doi: 10.1021/acs.jafc.9b02875. Epub 2019 Aug 1.
Glutathione -transferases (GSTs) play an active role in the development of drug resistance by numerous cancer cells, including melanoma cells, which is a major cause of chemotherapy failure. As part of our continuous effort to explore why dietary polyphenols bearing the catechol moiety (dietary catechols) show usually anticancer activity, catechol-type diphenylbutadiene (3,4-DHB) was selected as a model of dietary catechols to probe whether they work as pro-oxidative chemosensitizers via GST inhibition in melanoma cells. It was found that, in human melanoma A375 cells, 3,4-DHB is easily converted to its -quinone via copper-containing tyrosinase-mediated two-electron oxidation along with generation of reactive oxygen species (ROS) derived from the oxidation; the resulting -quinone and ROS are responsible for its ability to sensitize the cisplatin-resistant cells by inhibiting GST, followed by induction of apoptosis in an ASK1-JNK/p38 signaling cascade and mitochondria-dependent pathway. This work provides further evidence to support that dietary catechols exhibit antimelanoma activity by virtue of their tyrosinase-dependent pro-oxidative role and gives useful information for designing polyphenol-inspired GST inhibitors and sensitizers in chemotherapy against melanoma.
谷胱甘肽转移酶（GSTs）在许多癌细胞（包括黑色素瘤细胞）的耐药性发展中发挥着积极作用，这是化疗失败的主要原因。作为我们不断探索为什么含有儿茶酚部分的膳食多酚（膳食儿茶素）通常具有抗癌活性的一部分，儿茶酚型二苯丁二烯（3,4-DHB）被选为膳食儿茶素的模型，以探究它们是否通过抑制黑色素瘤细胞中的 GST 作为促氧化化学增敏剂发挥作用。研究发现，在人黑色素瘤 A375 细胞中，3,4-DHB 很容易通过含铜酪氨酸酶介导的两电子氧化转化为其醌，同时产生来自氧化的活性氧（ROS）；由此产生的醌和 ROS 负责通过抑制 GST 使顺铂耐药细胞敏感化，随后通过 ASK1-JNK/p38 信号级联和线粒体依赖性途径诱导细胞凋亡。这项工作进一步证明了膳食儿茶素通过其酪氨酸酶依赖性促氧化作用发挥抗黑色素瘤活性，并为设计基于多酚的 GST 抑制剂和化学增敏剂以对抗黑色素瘤提供了有用信息。
