Multiple antitumor effects of picropodophyllin in colon carcinoma cell lines: clinical implications.
Multiple antitumor effects of picropodophyllin in colon carcinoma cell lines: clinical implications.
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DOI：
10.3892/ijo.2011.1281
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发表时间：
2012-04
影响因子：
5.2
通讯作者：
Strömberg T
中科院分区：
文献类型：
--
作者：
Feng X;Aleem E;Lin Y;Axelson M;Larsson O;Strömberg T
虽然结直肠癌可以通过化疗/放射治疗和手术等传统方法成功治疗，但相当数量的病例，特别是那些有肝转移的病例，仍然是无法治愈的。因此，新的治疗方法是必要的。IGF-1R及其配体，主要是IGF-1和IGF-2，被认为在结肠/直肠腺癌细胞的增殖、存活和迁移中起关键作用。因此，干扰IGF-1R介导的信号转导可能是治疗这种恶性肿瘤的一种选择。在这项研究中，对48例结直肠癌患者配对的半定量RT-PCR分析显示，肿瘤IGF-1R和IGF-2mRNA显著过表达。基质金属蛋白酶-7的过度表达与组织学参数显著相关。基于这些发现，我们评估了IGF-1R抑制的环木脂素鬼臼蛋白(PPP)在四种结肠癌细胞株HT-29、HCT-116、DLD-1和Caco-2中的作用。PPP强烈抑制所有细胞系的增殖和迁移，且呈剂量依赖关系。然而，当暴露于0.5μM PPP时，与实验开始时的细胞数量相比，只有HT-29显示出活细胞的净减少，这一发现与IGF1R、AKT和ERK的表达/磷酸化降低相一致。该细胞还表现出PPP诱导的基质金属蛋白酶-7和基质金属蛋白酶-9的下调。与DLD-1和HCT-116细胞株相似，HT-29细胞对PPP的反应也表现出大量的细胞脱落。虽然PPP对细胞的净减少似乎需要IGF-1R、AKT和ERK1/2的同步下调，但部分抗肿瘤作用可能是由其他可能与IGF-1R无关的机制解释的(S)。PPP对结肠癌细胞的多种抑制作用，以及其在体内的低毒性，使其成为治疗这种疾病的有前途的候选药物。
Although colorectal cancer can be successfully treated by conventional strategies such as chemo/radiotherapy and surgery, a substantial number of cases, in particular those with liver metastases, remain incurable. Therefore, novel treatment approaches are warranted. The IGF-1R and its ligands, mainly IGF-1 and IGF-2, have been suggested to play pivotal roles in proliferation, survival and migration of adenocarcinoma cells of the colon/rectum. Therefore, interference with IGF-1R-mediated signaling may represent a therapeutic option for this malignancy. In this study, semi-quantitative RT-PCR analyses of 48 paired, colorectal cancer patient samples showed significant overexpression of tumor IGF-1R and IGF-2 mRNA. There was also an overexpression of MMP-7, which was significantly correlated with histopathological parameters. Based on these findings, the effect of the IGF-1R-inhibitory cyclolignan picropodophyllin (PPP) was assessed in the four colon carcinoma cell lines HT-29, HCT-116, DLD-1 and CaCO-2. PPP strongly and dose-dependently inhibited proliferation and migration in all cell lines. However, when exposed to 0.5 μM PPP, only HT-29 showed a net decrease of viable cells as compared with the cell number at the beginning of the experiment, a finding that coincided with decreased expression/phosphorylation of IGF-1R, AKT and ERK. This cell line also exhibited PPP-induced downregulation of MMP-7 and MMP-9. Similar to the DLD-1 and HCT-116 cell lines, HT-29 also showed substantial cell detachment in response to PPP. Although a net reduction of cells by PPP seems to require a synchronized downregulation of IGF-1R, AKT and ERK1/2, part of the antitumor effect may be explained by other, possibly IGF-1R-unrelated mechanism(s). Such a multitude of inhibitory effects of PPP in colon cancer cells together with its low toxicity in vivo makes it a promising drug candidate in the treatment of this disease.
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影响因子：
168.9
作者：
Midgley, R;Kerr, D
通讯作者：
Kerr, D
影响因子：
4.6
作者：
NEWELL, KJ;WITTY, JP;MATRISIAN, LM
通讯作者：
MATRISIAN, LM
影响因子：
5.7
作者：
Duan Z;Choy E;Harmon D;Yang C;Ryu K;Schwab J;Mankin H;Hornicek FJ
通讯作者：
Hornicek FJ
影响因子：
254.7
作者：
Parkin, DM;Bray, F;Pisani, P
通讯作者：
Pisani, P
影响因子：
3.9
作者：
Belfiore, A;Pandini, G;Vigneri, R
通讯作者：
Vigneri, R