Aloperine executes antitumor effects against multiple myeloma through dual apoptotic mechanisms.
Aloperine executes antitumor effects against multiple myeloma through dual apoptotic mechanisms.
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Aloperine 通过双重细胞凋亡机制对多发性骨髓瘤发挥抗肿瘤作用。
DOI：
10.1186/s13045-015-0120-x
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发表时间：
2015-03-15
影响因子：
28.5
通讯作者：
Zhou Y
中科院分区：
文献类型：
--
作者：
Wang H;Yang S;Zhou H;Sun M;Du L;Wei M;Luo M;Huang J;Deng H;Feng Y;Huang J;Zhou Y
苦参碱是一种从苦参中分离出来的天然生物碱成分，在体外和体内均具有抗炎作用。我们的研究小组之前已经证明了aloperine可以显著诱导结肠癌SW480和HCT116细胞的凋亡。然而，其特异性靶点在多发性骨髓瘤（MM）中仍有待发现，尚未进行研究。分别在体外和体内测试了人类骨髓瘤细胞株（n = 8）、原发性骨髓瘤细胞（n = 12）、耐药骨髓瘤细胞株（n = 2）和动物模型对aloperine的增殖和凋亡敏感性。我们还研究了aloperine引发的凋亡通路的功能机制。即使在增殖细胞因子白介素-6和胰岛素样生长因子i存在的情况下，丙operine也以剂量和时间依赖的方式诱导MM细胞死亡。机制研究表明，丙operine不仅激活caspase-8，降低fadd样白介素-1β-转换酶（FLICE）样抑制蛋白长（FLIPL）和FLICE-抑制蛋白（FLIPS）的表达，还激活caspase-9，降低磷酸化(p)- pten的表达。此外，aloperine共同激活caspase-8/细胞flice抑制蛋白(cFLIP)-和caspase-9/p-PTEN/p- akt依赖性凋亡通路，导致克隆生存的不可逆抑制。Aloperine与肿瘤坏死因子相关的凋亡诱导配体（TRAIL）或硼特佐米一起诱导MM细胞凋亡。U266异种移植肿瘤模型和5T33 MM细胞均显示出aloperine的抗肿瘤作用，动物对该药物表现出良好的耐受性和较少的不良反应。丙operine对MM细胞具有多方面的抗肿瘤作用。我们的数据支持丙戊酸用于MM治疗的临床开发。本文的在线版本（doi:10.1186/s13045-015-0120-x）包含补充材料，仅供授权用户使用。
Aloperine, a natural alkaloid constituent isolated from the herb Sophora alopecuroides displays anti-inflammatory properties in vitro and in vivo. Our group previously demonstrated that aloperine significantly induced apoptosis in colon cancer SW480 and HCT116 cells. However, its specific target(s) remain to be discovered in multiple myeloma (MM) and have not been investigated. Human myeloma cell lines (n = 8), primary myeloma cells (n = 12), drug-resistant myeloma cell lines (n = 2), and animal models were tested for their sensitivity to aloperine in terms of proliferation and apoptosis both in vitro and in vivo, respectively. We also examined the functional mechanisms underlying the apoptotic pathways triggered by aloperine. Aloperine induced MM cell death in a dose- and time-dependent manner, even in the presence of the proliferative cytokines interleukin-6 and insulin-like growth factor I. Mechanistic studies revealed that aloperine not only activated caspase-8 and reduced the expression of FADD-like interleukin-1β-converting enzyme (FLICE)-like inhibitory protein long (FLIPL) and FLICE-inhibitory proteins (FLIPS) but also activated caspase-9 and decreased the expression of phosphorylated (p)-PTEN. Moreover, co-activation of the caspase-8/cellular FLICE-inhibitory protein (cFLIP)- and caspase-9/p-PTEN/p-AKT-dependent apoptotic pathways by aloperine caused irreversible inhibition of clonogenic survival. Aloperine induce more MM apoptosis with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or borterzomib. A U266 xenograft tumor model and 5T33 MM cells recapitulated the antitumor efficacy of aloperine, and the animals displayed excellent tolerance of the drug and few adverse effects. Aloperine has multifaceted antitumor effects on MM cells. Our data support the clinical development of aloperine for MM therapy. The online version of this article (doi:10.1186/s13045-015-0120-x) contains supplementary material, which is available to authorized users.
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影响因子：
8.8
作者：
Manning, L S;Berger, J D;O'Donoghue, H L;Sheridan, G N;Claringbold, P G;Turner, J H
通讯作者：
Turner, J H
影响因子：
10.1
作者：
Noll, Jacqueline E.;Williams, Sharon A.;Zannettino, Andrew C. W.
通讯作者：
Zannettino, Andrew C. W.
影响因子：
2.6
作者：
Alici, E;Konstantinidis, KV;Abedi-Valugerdi, M
通讯作者：
Abedi-Valugerdi, M
影响因子：
11.2
作者：
Liu, Xiangguo;Yue, Ping;Sun, Shi-Yong
通讯作者：
Sun, Shi-Yong
影响因子：
4.8
作者：
Koenig, Andreas;Buskiewicz, Iwona A.;Budd, Ralph C.
通讯作者：
Budd, Ralph C.