Identification of Catechol-Type Diphenylbutadiene as a Tyrosinase-Activated Pro-oxidative Chemosensitizer against Melanoma A375 Cells via Glutathione S-Transferase Inhibition.

Glutathione S-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 ortho-quinone via copper-containing tyrosinase-mediated two-electron oxidation along with generation of reactive oxygen species (ROS) derived from the oxidation; the resulting ortho-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.

[Effect of Wenyang Huazhuo Tongluo recipe contained serum on proliferation and cell cycle of systemic sclerosis skin fibroblasts].

OBJECTIVE: To investigate the effect of "Wenyang Huazhuo Tongluo recipe" (WYHZTLR) on proliferation and cell cycle of systemic sclerosis (SSc) skin fibroblasts in vitro by serum pharmacologic technique. METHODS: Prednisone, D-penicillamine and WYHZTLR contained serum from patients with SSc were respectively added into cultured normal dermal fibroblast cell-line and SSc lesional dermal fibroblast cell-line. Then the cells were incubated for 48 hours. Cell proliferation and cell cycle were examined by methyl thiazolyl tetrazolium (MTT) assay and flow cytometry, respectively. RESULTS: Western medicine Chinese medicine and integrated Chinese and western medicine could markedly inhibit the proliferation of normal dermal fibroblasts and SSc lesional dermal fibroblasts in vitro compared with control group (P < 0.05 or P < 0.01). But 20% serum in integrated Chinese and western medicine group could markedly inhibit the proliferation of fibroblasts compared with western medicine group (P < 0.01). Different drug-contained serum of WYHZTLR could markedly increase the percentage of G0-G1 stage cells (P < 0.01) and depress the percentage of sphase cells and G2-M stage cells compared with control group (P < 0.05 or P < 0.01). CONCLUSION: WYHZTLR can block the progression of SSc skin fibroblasts into sphase and G2-M stage and inhibit the proliferation of SSc skin fibroblasts, and WYHZTLR was unselectively interfered with normal and SSc fibroblasts in vitro.