Apoptosis-inducing effect of erlotinib is potentiated by 3,3′-diindolylmethane in vitro and in vivo using an orthotopic model of pancreatic cancer (Retracted article. See vol. 17, pg. 2266, 2018)
Apoptosis-inducing effect of erlotinib is potentiated by 3,3′-diindolylmethane in vitro and in vivo using an orthotopic model of pancreatic cancer (Retracted article. See vol. 17, pg. 2266, 2018)
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DOI：
10.1158/1535-7163.mct-08-0354
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发表时间：
2008-06-01
影响因子：
5.7
通讯作者：
Sarkar, Fazlul H.
中科院分区：
文献类型：
--
作者：
Ali, Shadan;Banerjee, Sanjeev;Sarkar, Fazlul H.
表皮生长因子受体（EGFR）酪氨酸激酶抑制剂阻断EGFR不足以有效的抗肿瘤活性，因为独立激活的生存途径。因此，多靶点方法可能会改善抗EGFR治疗的结果。在本研究中，我们使用原位动物肿瘤模型在体外和体内测定了3，3 '-二吲哚基甲烷（Bioresponse BR-DIM，简称B-DIM）（一种生物利用度更高的DIM制剂）对厄洛替尼细胞活力和细胞凋亡的影响。用B-DIM（20 μ mol/L）、厄洛替尼（2 μ mol/L）和联合用药处理具有不同水平EGFR和核因子-κ B（NF-κ B）DNA结合活性的BxPC-3和MIAPaCa细胞。用3-（4，5-二甲基噻唑-2-基）-2，5-二苯基四氮唑溴化物和组蛋白-DNA ELISA检测细胞存活和凋亡，用电泳迁移率变动分析检测NF-κ B DNA结合活性。我们发现，与单独使用厄洛替尼和B-DIM相比，厄洛替尼和B-DIM联合使用可显著降低BxPC-3细胞中3-（4，5-二甲基噻唑-2-基）-2，5-二苯基溴化四氮唑和克隆形成试验的细胞活力、诱导细胞凋亡、下调EGFR磷酸化、NF-κ B DNA结合活性和抗细胞凋亡基因的表达。相反，通过类似的处理，在MIAPaCa细胞中没有观察到这种效果。最重要的是，这些体外结果在动物模型中重现，表明B-DIM与厄洛替尼组合作为抗肿瘤剂比单独使用任一种药物有效得多。这些结果表明，B-DIM的使用可能是一个有用的策略，以实现更好的治疗结果的EGFR和NF-κ B活化状态的患者在他们的肿瘤。
Blockade of epidermal growth factor receptor (EGFR) by EGFR tyrosine kinase inhibitors is insufficient for effective antitumor activity because of independently activated survival pathways. A multitargeted approach may therefore improve the outcome of anti-EGFR therapies. In the present study, we determined the effects of 3,3'-diindolylmethane (Bioresponse BR-DIM referred to as B-DIM), a formulated DIM with greater bioavailability on cell viability and apoptosis with erlotinib in vitro and in vivo using an orthotopic animal tumor model. BxPC-3 and MIAPaCa cells with varying levels of EGFR and nuclear factor-kappa B (NF-kappa B) DNA-binding activity were treated with B-DIM (20 mu mol/L), erlotinib (2 mu mol/L), and the combination. Cell survival and apoptosis was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and histone-DNA ELISA, Electrophoretic mobility shift assay was used to evaluate NF-kappa B DNA-binding activity. We found significant reduction in cell viability by both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and clonogenic assays, induction of apoptosis, down-regulation of EGFR phosphorylation, NF-kappa B DNA-binding activity, and expression of antiapoptotic genes in BxPC-3 cells when treated with the combination of erlotinib and B-DIM compared with either agent alone. In contrast, no such effect was observed in MIAPaCa cells by similar treatment. Most importantly, these in vitro results were recapitulated in animal model showing that B-DIM in combination with erlotinib was much more effective as an antitumor agent compared with either agent alone. These results suggest that the utilization of B-DIM could be a useful strategy for achieving better treatment outcome in patients with activated status of EGFR and NF-kappa B in their tumors.