SKLB-M8 Induces Apoptosis Through the AKT/mTOR Signaling Pathway in Melanoma Models and Inhibits Angiogenesis With Decrease of ERK1/2 Phosphorylation

Journal of Pharmacological Sciences

Lijuan Chen²  Jiaolin Wen²  Xia Cheng²  Yinfeng Dong²  Kun Yu²  Chunlai Nie²  Feng Ma¹  Jingjing Wang²  Wenshuang Wu²  Minghai Tang²  Fang Wang²  Zhuang Yang² 

[1] Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, China;State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, China

关键词: melanoma;    anti-angiogenesis;    p53;    AKT;    ERK;   

DOI  :  10.1254/jphs.14077FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(41)Cited-By(9)Supplementary materials(1)SKLB-M8, a derivative of millepachine, showed significant anti-proliferative effects in melanoma cell lines. In this study, we investigated the anti-melanoma and anti-angiogenic activity of SKLB-M8 on three melanoma cell lines (A2058, CHL-1, and B16F10) and human umbilical vein endothelial cells (HUVECs). In vitro, SKLB-M8 showed anti-proliferative activity with IC50 values of 0.07, 0.25, and 0.88 μM in A2058, CHL-1, and B16F10 cell lines, respectively. Flow cytometory analysis showed that SKLB-M8 induced G2/M arrest in three melanoma cell lines, and western blotting demonstrated that SKLB-M8 down-regulated the expression of cdc2, up-regulated p53 in A2058 and CHL-1 cells, and triggered cell apoptosis through down-regulating AKT and phosphorylated mTOR (p-mTOR). SKLB-M8 also inhibited HUVEC proliferation, migration, invasion, and tube formation in vitro with the inhibition of phosphorylated ERK1/2 (p-ERK1/2). In vivo, alginate-encapsulated tumor cell assay revealed that SKLB-M8 suppressed B16F10 tumor angiogenesis. In CHL-1- and B16F10-tumor–bearing mouse models, SKLB-M8 inhibited tumor growth by oral treatment with less toxicity. CD31 immunofluoresence staining and caspase-3 immunohistochemistry indicated that SKLB-M8 inhibited melanoma tumor growth by targeting angiogenesis and inducing caspase3-dependent apoptosis. SKLB-M8 might be a potential anti-melanoma drug candidate.

【 授权许可】

Unknown