(--)-Xanthatin selectively induces GADD45γ and stimulates caspase-independent cell death in human breast cancer MDA-MB-231 cells.
(--)-Xanthatin selectively induces GADD45γ and stimulates caspase-independent cell death in human breast cancer MDA-MB-231 cells.
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DOI：
10.1021/tx200046s
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发表时间：
2011-06-20
影响因子：
4.1
通讯作者：
Aramaki H
中科院分区：
文献类型：
--
作者：
Takeda S;Matsuo K;Yaji K;Okajima-Miyazaki S;Harada M;Miyoshi H;Okamoto Y;Amamoto T;Shindo M;Omiecinski CJ;Aramaki H
含外-亚甲基内酯基团的化合物，例如（-）-黄嘌呤，存在于多种生物活性天然产物中，包括苍耳（苍耳）的提取物。据报道，这些物质具有多种功能活性，表现出抗炎、抗疟疾和抗癌潜力。在这项研究中，我们合成了六种结构相关的含有外亚甲基内酯部分的黄原胶，包括（−）-黄嘌呤和（+）-8-表黄嘌呤，并研究了这些化学成分明确的物质对高度侵袭性和法尼基转移酶抑制剂（FTI）抗性的MDA-MB-231癌细胞系的影响。结果表明，（-）-黄嘌呤是一种高效的MDA-MB-231细胞生长抑制剂，可诱导半胱天冬酶非依赖性细胞死亡，并且这些作用与FTase抑制无关。此外，我们的研究结果表明，在GADD 45亚型中，GADD 45 γ被（-）-黄嘌呤选择性诱导，并且GADD 45 γ引发的JNK和p38信号通路至少部分参与介导该试剂的生长抑制和潜在抗癌活性。鉴于GADD 45 γ越来越多地被认为具有肿瘤抑制功能，本文的结果表明，（-）-黄嘌呤可能具有作为人类癌细胞中GADD 45 γ的选择性诱导剂的治疗价值，特别是在FTI耐药的侵袭性乳腺癌中。
exo-Methylene lactone group-containing compounds, such as (−)-xanthatin, are present in a large variety of biologically active natural products, including extracts of Xanthium strumarium (Cocklebur). These substances are reported to possess diverse functional activities, exhibiting anti-inflammatory, antimalarial, and anticancer potential. In this study, we synthesized six structurally related xanthanolides containing exo-methylene lactone moieties, including (−)-xanthatin and (+)-8-epi-xanthatin, and examined the effects of these chemically defined substances on the highly aggressive and farnesyltransferase inhibitor (FTI)-resistant MDA-MB-231 cancer cell line. The results obtained demonstrate that (−)-xanthatin was a highly effective inhibitor of MDA-MB-231 cell growth, inducing caspase-independent cell death, and that these effects were independent of FTase inhibition. Further, our results show that among the GADD45 isoforms, GADD45γ was selectively induced by (−)-xanthatin and that GADD45γ-primed JNK and p38 signaling pathways are, at least in part, involved in mediating the growth inhibition and potential anticancer activities of this agent. Given that GADD45γ is becoming increasingly recognized for its tumor suppressor function, the results presented here suggest the novel possibility that (−)-xanthatin may have therapeutic value as a selective inducer of GADD45γ in human cancer cells, in particular in FTI-resistant aggressive breast cancers.
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影响因子：
5.8
作者：
Hardcastle, IR;Rowlands, MG;Jarman, M
通讯作者：
Jarman, M
影响因子：
3.8
作者：
Herzig, MCS;Liang, HY;Woynarowski, JM
通讯作者：
Woynarowski, JM
影响因子：
4.8
作者：
Denoyelle, C;Albanese, P;Soria, C
通讯作者：
Soria, C
影响因子：
11.2
作者：
Miki, Yasuhiro;Suzuki, Takashi;Sasano, Hironobu
通讯作者：
Sasano, Hironobu
影响因子：
2.7
作者：
Janzowski, C;Glaab, V;Eisenbrand, G
通讯作者：
Eisenbrand, G