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Antitumor Activity of Americanin A Isolated from the Seeds of Phytolacca americana by Regulating the ATM/ATR Signaling Pathway and the Skp2–p27 Axis in Human Colon Cancer Cells
Journal of Natural Products ( IF 3.3 ) Pub Date : 2015-11-23 00:00:00 , DOI: 10.1021/acs.jnatprod.5b00743
Cholomi Jung 1 , Ji-Young Hong 1 , Song Yi Bae 1 , Sam Sik Kang 1 , Hyen Joo Park 1 , Sang Kook Lee 1
Journal of Natural Products ( IF 3.3 ) Pub Date : 2015-11-23 00:00:00 , DOI: 10.1021/acs.jnatprod.5b00743
Cholomi Jung 1 , Ji-Young Hong 1 , Song Yi Bae 1 , Sam Sik Kang 1 , Hyen Joo Park 1 , Sang Kook Lee 1
Affiliation
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The antiproliferative and antitumor activities of americanin A (1), a neolignan isolated from the seeds of Phytolacca americana, were investigated in human colon cancer cells. Compound 1 inhibited the proliferation of HCT116 human colon cancer cells both in vitro and in vivo. The induction of G2/M cell-cycle arrest by 1 was concomitant with regulation of the ataxia telangiectasia-mutated/ATM and Rad3-related (ATM/ATR) signaling pathway. Treatment with 1 activated ATM and ATR, initiating the subsequent signal transduction cascades that include checkpoint kinase 1 (Chk1), checkpoint kinase 2 (Chk2), and tumor suppressor p53. Another line of evidence underlined the significance of 1 in regulation of the S phase kinase-associated protein 2 (Skp2)–p27 axis. Compound 1 targeted selectively Skp2 for degradation and thereby stabilized p27. Therefore, compound 1 suppressed the activity of cyclin B1 and its partner cell division cycle 2 (cdc2) to prevent entry into mitosis. Furthermore, prolonged treatment with 1 induced apoptosis by producing excessive reactive oxygen species. The intraperitoneal administration of 1 inhibited the growth of HCT116 tumor xenografts in nude mice without any overt toxicity. Modulation of the ATM/ATR signaling pathway and the Skp2–p27 axis might be plausible mechanisms of action for the antiproliferative and antitumor activities of 1 in human colon cancer cells.
中文翻译：
通过调节人类结肠癌细胞中的ATM / ATR信号传导途径和Skp2-p27轴，从美洲疫霉菌种子中分离的Americanin A的抗肿瘤活性
在人类结肠癌细胞中研究了美洲菊A（1）的抗增殖和抗肿瘤活性，美洲菊A是从美洲疫霉种子中分离出来的一种新木脂素。化合物1在体外和体内均抑制HCT116人结肠癌细胞的增殖。G的诱导2 / M细胞周期停滞由1是伴随着所述共济失调毛细血管扩张症突变的/ ATM和RAD3相关（ATM / ATR）信号通路的调节。用1个激活的ATM和ATR进行治疗，启动随后的信号转导级联反应，包括检查点激酶1（Chk1），检查点激酶2（Chk2）和肿瘤抑制因子p53。另一条证据强调了在S期激酶相关蛋白2（Skp2）–p27轴的调控中为1。化合物1选择性靶向Skp2进行降解，从而稳定了p27。因此，化合物1抑制细胞周期蛋白B1的活性及其伴侣细胞分裂周期2（cdc2），以防止进入有丝分裂。此外，长期用1处理会产生过多的活性氧，从而诱导细胞凋亡。腹膜内给予1可抑制裸鼠中HCT116肿瘤异种移植物的生长，而没有任何明显的毒性。ATM / ATR信号通路和Skp2-p27轴的调节可能是1的抗增殖和抗肿瘤活性的合理作用机制。 在人类结肠癌细胞中。
更新日期：2015-11-23
中文翻译：
通过调节人类结肠癌细胞中的ATM / ATR信号传导途径和Skp2-p27轴，从美洲疫霉菌种子中分离的Americanin A的抗肿瘤活性
在人类结肠癌细胞中研究了美洲菊A（1）的抗增殖和抗肿瘤活性，美洲菊A是从美洲疫霉种子中分离出来的一种新木脂素。化合物1在体外和体内均抑制HCT116人结肠癌细胞的增殖。G的诱导2 / M细胞周期停滞由1是伴随着所述共济失调毛细血管扩张症突变的/ ATM和RAD3相关（ATM / ATR）信号通路的调节。用1个激活的ATM和ATR进行治疗，启动随后的信号转导级联反应，包括检查点激酶1（Chk1），检查点激酶2（Chk2）和肿瘤抑制因子p53。另一条证据强调了在S期激酶相关蛋白2（Skp2）–p27轴的调控中为1。化合物1选择性靶向Skp2进行降解，从而稳定了p27。因此，化合物1抑制细胞周期蛋白B1的活性及其伴侣细胞分裂周期2（cdc2），以防止进入有丝分裂。此外，长期用1处理会产生过多的活性氧，从而诱导细胞凋亡。腹膜内给予1可抑制裸鼠中HCT116肿瘤异种移植物的生长，而没有任何明显的毒性。ATM / ATR信号通路和Skp2-p27轴的调节可能是1的抗增殖和抗肿瘤活性的合理作用机制。 在人类结肠癌细胞中。
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