Deoxyarbutin displays antitumour activity against melanoma in vitro and in vivo through a p38-mediated mitochondria associated apoptotic pathway

Limei Ma,Zhihua Xing,Zeliang Wei,Yao Xu,Wen Huang,Hai Niu,Guang Xin

doi:10.1038/s41598-017-05416-8

Limei Ma, Zhihua Xing + Show 5 more

Open Access

https://doi.org/10.1038/s41598-017-05416-8

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Abstract

Deoxyarbutin (DeoxyArbutin, dA), a natural compound widely used in skin lighting, displayed selectively cytotoxicity in vitro. In the study, we found that dA significantly inhibited viability/proliferation of B16F10 melanoma cells, induced tumour cell arrest and apoptosis. Furthermore, dA triggered its pro-apoptosis through damaging the mitochondrial function (membrane potential loss, ATP depletion and ROS overload generation etc.) and activating caspase-9, PARP, caspase-3 and the phosphorylation of p38. Treatment with p38 agonist confirmed the involvement of p38 pathway triggered by dA in B16F10 cells. The in vivo finding also revealed that administration of dA significantly decreased the tumour volume and tumour metastasis in B16F10 xenograft model by inhibiting tumour proliferation and inducing tumour apoptosis. Importantly, the results indicated that dA was specific against tumour cell lines and had no observed systemic toxicity in vivo. Taken together, our study demonstrated that dA could combate tumour in vitro and in vivo by inhibiting the proliferation and metastasis of tumour via a p38-mediated mitochondria associated apoptotic pathway.

Highlights

Cutaneous melanoma is one of the most lethal and fastest growing forms of human cancers to affect a younger population[1, 2]
The effect of dA on the proliferation of various cell lines was determined by using a Cell Counting Kit-8 (CCK-8) or MTT (3-(4,5-dimethyl-2-thia-zolyl)-2, 5-diphenyl-2H-tetrazolium bromide) assay
Cell viability was separately evaluated in six normal cell lines (NIH/3T3, HS68, HK-2, L02, HLECs and Human Umbilical Vein cell line (HUVEC) cells) and two cancer cells (B16F10, LL/2), which had been treated with varying concentrations from 10 μM to 200 μM of dA for 24 h

Summary

Introduction

Cutaneous melanoma is one of the most lethal and fastest growing forms of human cancers to affect a younger population[1, 2]. MAP kinase family, especially involvement of p38, has been implicated in mitochondrial dysfunction and apoptotic pathway[26,27,28]. Several chemotherapeutic agents, such as nocodazole, vinblastine as well as taxol could activate p38 MAPK pathway and induce cell cycle arrest by affecting mitochondrial damage and ROS gerneation[29]. P38 and its mediated signaling are critical targets to answer ROS stress[30,31,32] Together, these findings suggest the potential role of p38 MAPK in anticancer therapy concerning mitochondria associated apoptotic pathway

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