Jatamanvaltrate P induces cell cycle arrest, apoptosis and autophagy in human breast cancer cells in vitro and in vivo
Jatamanvaltrate P induces cell cycle arrest, apoptosis and autophagy in human breast cancer cells in vitro and in vivo
复制标题
DOI：
10.1016/j.biopha.2017.02.065
复制
发表时间：
2017-05-01
影响因子：
7.5
通讯作者：
Zhao, Huajun
中科院分区：
文献类型：
--
作者：
Yang, Bo;Zhu, Rui;Zhao, Huajun
Jatamanvaltrate P是一种新的环烯醚萜酯类化合物，从传统的治疗神经系统疾病的药物蜘蛛香中分离得到。在这项研究中，我们发现Jatamanvaltrate P具有显着的抗肿瘤特性，因此评估了其对人乳腺癌细胞的体外和体内抗癌作用。Jatamanvaltrate P以浓度依赖性方式抑制MCF-7和三阴性乳腺癌（TNBC）细胞系（MDA-MB-231、MDA-MB-453和MDA-MB-468）的生长和增殖，同时对人乳腺上皮细胞（MCF-10A）显示出相对较低的细胞毒性。用Jatamanvaltrate P处理诱导TNBC中的G2/M期停滞和MCF-7细胞中的G 0/G1期停滞。对这种细胞毒性化合物的分子机制的进一步研究表明，Jatamanvaltrate P增强了PARP和caspase的切割，同时降低了细胞周期相关的Cyclin B1、Cyclin D1和Cdc-2的表达水平。它还激活自噬，如触发的自噬体形成和增加的LC 3-II水平所示。通过3-MA共处理的自噬抑制破坏了Jatamanvaltrate P诱导的细胞死亡。最后，Jatamanvaltrate P在MDA-MB-231异种移植物中表现出潜在的抗肿瘤作用，没有明显的毒性。这些结果表明Jatamanvaltrate P是一种潜在的乳腺癌治疗药物，为开发该化合物作为新型化疗药物提供了基础。(C)2017 Elsevier Masson SAS。All rights reserved.
Jatamanvaltrate P is a novel iridoid ester isolated from Valeriana jatamansi Jones, a traditional medicine used to treat nervous disorders. In this study, we found that Jatamanvaltrate P possessed notable antitumor properties and therefore evaluated its anticancer effects against human breast cancer cells in vitro and in vivo. Jatamanvaltrate P inhibited the growth and proliferation of MCF-7 and triple-negative breast cancer (TNBC) cell lines (MDA-MB-231, MDA-MB-453 and MDA-MB-468) in a concentration-dependent manner, while displayed relatively low cytotoxicity to human breast epithelial cells (MCF-10A). Treatment with Jatamanvaltrate P induced G2/M-phase arrest in TNBC and G0/G1-phase arrest in MCF-7 cells. Further study of the molecular mechanisms of this cytotoxic compound demonstrated that Jatamanvaltrate P enhanced cleavage of PARP and caspases, while decreased the expression levels of cell cycle-related Cyclin B1, Cyclin D1 and Cdc-2. It also activated autophagy, as indicated by the triggered autophagosome formation and increased LC3-II levels. Autophagy inhibition by 3-MA co-treatment undermined Jatamanvaltrate P-induced cell death. Finally, Jatamanvaltrate P exhibited a potential antitumor effect in MDA-MB-231 xenografts without apparent toxicity. These results suggest that Jatamanvaltrate P is a potential therapeutic agent for breast cancer, providing a basis for development of the compound as a novel chemotherapeutic agent. (C) 2017 Elsevier Masson SAS. All rights reserved.