Aliphatic acetogenin constituents of avocado fruits inhibit human oral cancer cell proliferation by targeting the EGFR/RAS/RAF/MEK/ERK1/2 pathway.
Aliphatic acetogenin constituents of avocado fruits inhibit human oral cancer cell proliferation by targeting the EGFR/RAS/RAF/MEK/ERK1/2 pathway.
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DOI：
10.1016/j.bbrc.2011.05.027
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发表时间：
2011-06-10
影响因子：
3.1
通讯作者：
Ding H
中科院分区：
文献类型：
--
作者：
D'Ambrosio SM;Han C;Pan L;Kinghorn AD;Ding H
牛油果作为人类饮食的一部分被食用，其提取物显示出对各种类型的人类癌细胞的生长抑制作用，尽管人们对单个成分的有效性及其潜在机制知之甚少。利用牛油果果肉的活性引导分离，鉴定出一种氯仿可溶性提取物（D003），对人类口腔癌前和恶性细胞系具有很高的疗效。从该提取物中分离到两个已知结构的脂肪族乙酰原，化合物1 [(2S,4S)-2,4-二羟基庚-16-乙酸烯基]和2 [(2S,4S)-2,4-二羟基庚-16-乙酸乙烯基]。在这项研究中，我们首次发现这种氯仿提取物的生长抑制作用是由于阻断EGFR/RAS/RAF/MEK/ERK1/2癌症通路中EGFR （Tyr1173）、c-RAF （Ser338）和ERK1/2 （Thr202/Tyr204）的磷酸化。化合物1和2均抑制c-RAF （Ser338）和ERK1/2 （Thr202/Tyr204）的磷酸化。化合物2，而不是化合物1，可以阻止egf诱导的EGFR （Tyr1173）的激活。当化合物1和2联合使用时，它们协同抑制c-RAF （Ser338）和ERK1/2 （Thr202/Tyr204）磷酸化，并抑制人口腔癌细胞增殖。目前的数据表明，鳄梨果实的潜在抗癌活性是由于特定脂肪族乙酰原的组合，靶向EGFR/RAS/RAF/MEK/ERK1/2癌症途径的两个关键成分。
Avocado (Persea americana) fruits are consumed as part of the human diet and extracts have shown growth inhibitory effects in various types of human cancer cells, although the effectiveness of individual components and their underlying mechanism are poorly understood. Using activity-guided fractionation of the flesh of avocado fruits, a chloroform-soluble extract (D003), was identified that exhibited high efficacy towards premalignant and malignant human oral cancer cell lines. From this extract, two aliphatic acetogenins of previously known structure were isolated, compounds 1 [(2S,4S)-2,4-dihydroxyheptadec-16-enyl acetate] and 2 [(2S,4S)-2,4-dihydroxyheptadec-16-ynyl acetate]. In this study, we show for the first time that the growth inhibitory efficacy of this chloroform extract is due to blocking the phosphorylation of EGFR (Tyr1173), c-RAF (Ser338), and ERK1/2 (Thr202/Tyr204) in the EGFR/RAS/RAF/MEK/ERK1/2 cancer pathway. Compound 1 and 2 both inhibited phosphorylation of c-RAF (Ser338) and ERK1/2 (Thr202/Tyr204). Compound 2, but not compound 1, prevented EGF-induced activation of EGFR (Tyr1173). When compounds 1 and 2 were combined they synergistically inhibited c-RAF (Ser338) and ERK1/2 (Thr202/Tyr204) phosphorylation, and human oral cancer cell proliferation. The present data suggest that the potential anticancer activity of avocado fruits is due to a combination of specific aliphatic acetogenins that target two key components of the EGFR/RAS/RAF/MEK/ERK1/2 cancer pathway.
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影响因子：
3.8
作者：
Domergue, F;Helms, GL;Browse, J
通讯作者：
Browse, J
影响因子：
6.1
作者：
Lee, H;Li, D;Milo, GE
通讯作者：
Milo, GE
影响因子：
2.9
作者：
Han, CH;Ding, HM;D'Ambrosio, SM
通讯作者：
D'Ambrosio, SM
影响因子：
51.1
作者：
Linardou, Helena;Dahabreh, Issa J.;Murray, Samuel
通讯作者：
Murray, Samuel
影响因子：
45.3
作者：
Allegra, Carmen J.;Jessup, J. Milburn;Schilsky, Richard L.
通讯作者：
Schilsky, Richard L.