Medicinal Chemistry

N-Acetyl-L-tyrosine enhances the Inhibition Sensitivity of Procarbazine against Melanoma Targeted Tyrosinase without the Increase of Toxicity

Abstract

Yuanlin Liu, Wenda Zhu, Chao Zhang, Yanbing Li, Rikang Wang, Yepu He, Fengxia Yan, Meili Yin, Zhenyou Jiang and Heru Chen*

Procarbazine (Pcb) is a component of a chemotherapeutic cocktail in the treatment of melanoma. Unfortunately, Pcb brings about very common adverse effects. In this study, we tried to improve the therapeutically efficacy of Pcb by combination of N-acetyl-L-tyrosine (NAT). We investigated the effect of Pcb/NAT and its underlying mechanism in melanoma via MTT assay, cell cycle assay, ΔΨ_m assay, Western blotting and in vivo animal model. It was found that combination of Pcb with NAT in 1:1 mole ratio (Pcb/NAT) enhanced the inhibition sensitivity against murine melanoma cells B16/F10 with IC50 value changed from 31.9 ± 1.1 to 14.2 ± 1.1 μM. Similar result was found in K1735 cell line. Compared to Pcb solely, the inhibitory rate of Pcb/NAT against B16/F10-bearing tumor in C57BL/6 mice was 89.4% by 5.8% increase; whilst the volume inhibition rate was 95.6% by 10.1% increase. Pcb/NAT was confirmed with more significant effects on cell differentiation, apoptosis, cycle and mitochondrial membrane potential in B16/F10 cells than Pcb solely. It was found that the present of NAT increased the transformation of Pcb. Involvement of NAT intensified the upregulation of tyrosinase activity/protein level, and the expression of GADPH in vitro and in vivo. Pcb/NAT also enhanced the activation of p53 leading to a more decrease of Bcl-2/Bax ratio than Pcb solely. It was found that sensitivity increase of Pcb/NAT against melanoma brings no increase in toxicity. All the data support that Pcb/NAT is a promising anti-melanoma agent to replace Pcb.