The cinnamon-derived Michael acceptor cinnamic aldehyde impairs melanoma cell proliferation, invasiveness, and tumor growth.
The cinnamon-derived Michael acceptor cinnamic aldehyde impairs melanoma cell proliferation, invasiveness, and tumor growth.
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DOI：
10.1016/j.freeradbiomed.2008.10.025
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发表时间：
2009-01-15
影响因子：
7.4
通讯作者：
Wondrak, Georg T.
中科院分区：
文献类型：
--
作者：
Cabello, Christopher M.;Bair, Warner B., III;Lamore, Sarah D.;Ley, Stephanie;Bause, Alexandra S.;Azimian, Sara;Wondrak, Georg T.
关键词：
癌细胞中的氧化还原失调代表了一种化学脆弱性，可以通过氧化剂氧化还原干预来靶向。因此，含有亲电Michael受体药效团的膳食成分可能显示出有希望的化学预防和化学治疗抗癌活性。在这里，我们证明了肉桂衍生的膳食迈克尔受体反式肉桂醛（CA）损害黑色素瘤细胞增殖和肿瘤生长。在人类A375黑色素瘤scid -小鼠异种移植模型中证明了使用高剂量CA （120 mg/kg, p.o, q.d， 10天）进行治疗干预的可行性。低微摩尔浓度（IC50 < 10 μM）的CA，但不是密切相关的缺乏Michael受体活性的CA衍生物，抑制了人类转移性黑色素瘤细胞系（A375, G361， LOX）的增殖，导致G1细胞周期停滞，细胞内ROS升高，侵袭性受损。表达阵列分析显示，CA诱导A375细胞的氧化应激反应，上调血红素氧化酶-1 （HMOX1）、硫氧还蛋白1同源物（SRXN1）、硫氧还蛋白还原酶1 （TXNRD1）和其他基因，包括细胞周期调节因子和应激反应性肿瘤抑制基因周期蛋白依赖性激酶抑制剂1A (CDKN1A)，这是G1期阻滞的关键介质。CA抑制了A375细胞中NFκB的转录活性和tnf α诱导的IL-8的产生，而非Michael-inactive衍生物。这些发现支持了以前未被认识到的CA作为具有潜在抗癌活性的膳食Michael受体的作用。
Redox dysregulation in cancer cells represents a chemical vulnerability that can be targeted by prooxidant redox intervention. Dietary constituents that contain an electrophilic Michael acceptor pharmacophore may therefore display promising chemopreventive and chemotherapeutic anti-cancer activity. Here, we demonstrate that the cinnamon-derived dietary Michael acceptor trans-cinnamic aldehyde (CA) impairs melanoma cell proliferation and tumor growth. Feasibility of therapeutic intervention using high doses of CA (120 mg/kg, p.o., q.d., 10 days) was demonstrated in a human A375 melanoma SCID-mouse xenograft model. Low micromolar concentrations (IC50 < 10 μM) of CA, but not closely related CA-derivatives devoid of Michael acceptor activity, suppressed proliferation of human metastatic melanoma cell lines (A375, G361, LOX) with G1 cell cycle arrest, elevated intracellular ROS, and impaired invasiveness. Expression array analysis revealed that CA induced an oxidative stress response in A375 cells, up-regulating heme oxygenase-1 (HMOX1), sulfiredoxin 1 homolog (SRXN1), thioredoxin reductase 1 (TXNRD1), and other genes including the cell cycle regulator and stress-responsive tumor suppressor gene cyclin-dependent kinase inhibitor 1A (CDKN1A), a key mediator of G1 phase arrest. CA, but not Michael-inactive derivatives, inhibited NFκB transcriptional activity and TNFα-induced IL-8 production in A375 cells. These findings support a previously unrecognized role of CA as a dietary Michael acceptor with potential anticancer activity.
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影响因子：
4.6
作者：
Han, Eun-Soo;Muller, Florian L.;Richardson, Arlan
通讯作者：
Richardson, Arlan
DOI：
10.1152/ajpcell.2001.280.3.c659
发表时间：
2001-03-01
影响因子：
5.5
作者：
Brar, SS;Kennedy, TP;Hoidal, JR
通讯作者：
Hoidal, JR
影响因子：
3.7
作者：
Maytin, EV;Ubeda, M;Habener, JF
通讯作者：
Habener, JF
影响因子：
6.1
作者：
Friedman, M;Kozukue, N;Harden, LA
通讯作者：
Harden, LA
影响因子：
11.5
作者：
Fruehauf, John P.;Meyskens, Frank L., Jr.
通讯作者：
Meyskens, Frank L., Jr.