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

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

Abstract.: 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 endothelia...

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Main Authors: Jingjing Wang, Zhuang Yang, Jiaolin Wen, Feng Ma, Fang Wang, Kun Yu, Minghai Tang, Wenshuang Wu, Yinfeng Dong, Xia Cheng, Chunlai Nie, Lijuan Chen
Format: Article
Language:English
Published: Elsevier 2014-04-01
Series:Journal of Pharmacological Sciences
Online Access:http://www.sciencedirect.com/science/article/pii/S134786131930074X
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spelling doaj-73fb9f1c0eea4d268f5a1e5375318cf02020-11-24T22:00:37ZengElsevierJournal of Pharmacological Sciences1347-86132014-04-011263198207SKLB-M8 Induces Apoptosis Through the AKT/mTOR Signaling Pathway in Melanoma Models and Inhibits Angiogenesis With Decrease of ERK1/2 PhosphorylationJingjing Wang0Zhuang Yang1Jiaolin Wen2Feng Ma3Fang Wang4Kun Yu5Minghai Tang6Wenshuang Wu7Yinfeng Dong8Xia Cheng9Chunlai Nie10Lijuan Chen11State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China; College of Chemistry, Sichuan University, Chengdu 610064, ChinaState Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, ChinaInstitute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, Chengdu 610081, ChinaState Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China; Corresponding authors. *aniecl1022@scu.edu.cn, *bchenlijuan125@163.comState Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China; Corresponding authors. *aniecl1022@scu.edu.cn, *bchenlijuan125@163.comAbstract.: 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.[Supplementary Figure: available only at http://dx.doi.org/10.1254/jphs.14077FP] Keywords:: melanoma, anti-angiogenesis, p53, AKT, ERKhttp://www.sciencedirect.com/science/article/pii/S134786131930074X
collection DOAJ
language English
format Article
sources DOAJ
author Jingjing Wang
Zhuang Yang
Jiaolin Wen
Feng Ma
Fang Wang
Kun Yu
Minghai Tang
Wenshuang Wu
Yinfeng Dong
Xia Cheng
Chunlai Nie
Lijuan Chen
spellingShingle Jingjing Wang
Zhuang Yang
Jiaolin Wen
Feng Ma
Fang Wang
Kun Yu
Minghai Tang
Wenshuang Wu
Yinfeng Dong
Xia Cheng
Chunlai Nie
Lijuan Chen
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
author_facet Jingjing Wang
Zhuang Yang
Jiaolin Wen
Feng Ma
Fang Wang
Kun Yu
Minghai Tang
Wenshuang Wu
Yinfeng Dong
Xia Cheng
Chunlai Nie
Lijuan Chen
author_sort Jingjing Wang
title SKLB-M8 Induces Apoptosis Through the AKT/mTOR Signaling Pathway in Melanoma Models and Inhibits Angiogenesis With Decrease of ERK1/2 Phosphorylation
title_short SKLB-M8 Induces Apoptosis Through the AKT/mTOR Signaling Pathway in Melanoma Models and Inhibits Angiogenesis With Decrease of ERK1/2 Phosphorylation
title_full SKLB-M8 Induces Apoptosis Through the AKT/mTOR Signaling Pathway in Melanoma Models and Inhibits Angiogenesis With Decrease of ERK1/2 Phosphorylation
title_fullStr SKLB-M8 Induces Apoptosis Through the AKT/mTOR Signaling Pathway in Melanoma Models and Inhibits Angiogenesis With Decrease of ERK1/2 Phosphorylation
title_full_unstemmed SKLB-M8 Induces Apoptosis Through the AKT/mTOR Signaling Pathway in Melanoma Models and Inhibits Angiogenesis With Decrease of ERK1/2 Phosphorylation
title_sort sklb-m8 induces apoptosis through the akt/mtor signaling pathway in melanoma models and inhibits angiogenesis with decrease of erk1/2 phosphorylation
publisher Elsevier
series Journal of Pharmacological Sciences
issn 1347-8613
publishDate 2014-04-01
description Abstract.: 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.[Supplementary Figure: available only at http://dx.doi.org/10.1254/jphs.14077FP] Keywords:: melanoma, anti-angiogenesis, p53, AKT, ERK
url http://www.sciencedirect.com/science/article/pii/S134786131930074X
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