Origanum majorana Ethanolic Extract Promotes Colorectal Cancer Cell Death by Triggering Abortive Autophagy and Activation of the Extrinsic Apoptotic Pathway
Origanum majorana Ethanolic Extract Promotes Colorectal Cancer Cell Death by Triggering Abortive Autophagy and Activation of the Extrinsic Apoptotic Pathway
复制标题
DOI：
10.3389/fonc.2019.00795
复制
发表时间：
2019-08-21
影响因子：
4.7
通讯作者：
Iratni, Rabah
中科院分区：
文献类型：
--
作者：
Benhalilou, Nehia;Alsamri, Halima;Iratni, Rabah
结直肠癌被认为是癌症死亡的第三大原因。本研究旨在探讨马郁兰乙醇提取物（Origanummajorana ethanolicextract，OME）对人大肠癌细胞的潜在抗肿瘤作用及其分子机制。我们发现，OME表现出强烈的抗增殖活性的浓度和时间依赖性的方式对两个人结直肠癌细胞系（HT-29和Caco-2）。OME抑制HT-29细胞的细胞活力、集落生长并诱导有丝分裂停滞。此外，OME诱导DNA损伤，引发流产性自噬，并激活caspase 3和7依赖性外源性凋亡途径，最有可能是通过激活TNF α途径。时程分析显示，DNA损伤发生伴随着流产的自噬后4小时的OME处理，而细胞凋亡被激活后，只有24小时。3-甲基腺嘌呤阻断自噬启动，部分挽救了OME诱导的细胞死亡。细胞存活率从对照组的37%上升到加入OME前用3-MA预处理的组的67%。然而，细胞凋亡的抑制对细胞活力的影响最小;它从对照组的37%上升到用Z-VAD-FMK预处理的组的43%。我们还发现，OME下调HT-29细胞中的生存素。我们的研究结果为O. majorana提取物至少通过诱导自噬和细胞凋亡具有强的抗结肠癌潜力。这些结果为O.结肠癌的治疗方法
Colorectal cancer is considered as the third leading cause of cancer death. In the present study, we investigated the potential anticancer effect and the molecular mechanism of Origanum majorana ethanolic extract (OME) against human colorectal cancer cells. We showed that OME exhibited strong anti-proliferative activity in a concentration- and time-dependent manner against two human colorectal cancer cell lines (HT-29 and Caco-2). OME inhibited cell viability, colony growth and induced mitotic arrest of HT-29 cells. Also, OME induced DNA damage, triggered abortive autophagy and activated a caspase 3 and 7-dependent extrinsic apoptotic pathway, most likely through activation of the TNF alpha pathway. Time-course analysis revealed that DNA damage occurred concomitantly with abortive autophagy after 4 h post-OME treatment while apoptosis was activated only 24 h later. Blockade of autophagy initiation, by 3-methyladenine, partially rescued OME-induced cell death. Cell viability arose from 37% in control group to 67% in group pre-treated with 3-MA before addition of OME. Inhibition of apoptosis, however, had a minimal effect on cell viability; it rose from 37% in control group to 43% in group pre-treated with Z-VAD-FMK. We also found that OME downregulated survivin in HT-29 cells. Our findings provide a strong evidence that O. majorana extract possesses strong anti-colon cancer potential, at least, through induction of autophagy and apoptosis. These finding provide the basis for therapeutic potential of O. majorana in the treatment of colon cancer.