Division of Hematology/Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA.
J Cell Biochem. 2010 May;110(1):171-81. doi: 10.1002/jcb.22523.
Inactivation of survival pathways such as NF-kappaB, cyclooxygenase (COX-2), or epidermal growth factor receptor (EGFR) signaling individually may not be sufficient for the treatment of advanced pancreatic cancer (PC) as suggested by recent clinical trials. 3,3'-Diindolylmethane (B-DIM) is an inhibitor of NF-kappaB and COX-2 and is a well-known chemopreventive agent. We hypothesized that the inhibition of NF-kappaB and COX-2 by B-DIM concurrently with the inhibition of EGFR by erlotinib will potentiate the anti-tumor effects of cytotoxic drug gemcitabine, which has been tested both in vitro and in vivo. Inhibition of viable cells in seven PC cell lines treated with B-DIM, erlotinib, or gemcitabine alone or their combinations was evaluated using 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Significant inhibition in cell viability was observed in PC cells expressing high levels of COX-2, EGFR, and NF-kappaB proteins. The observed inhibition was associated with an increase in apoptosis as assessed by ELISA. A significant down-regulation in the expression of COX-2, NF-kappaB, and EGFR in BxPC-3, COLO-357, and HPAC cells was observed, suggesting that simultaneous targeting of EGFR, NF-kappaB, and COX-2 is more effective than targeting either signaling pathway separately. Our in vitro results were further supported by in vivo studies showing that B-DIM in combination with erlotinib and gemcitabine was significantly more effective than individual agents. Based on our preclinical in vitro and in vivo results, we conclude that this multi-targeted combination could be developed for the treatment of PC patients whose tumors express high levels of COX-2, EGFR, and NF-kappaB.
NF-κB、环氧化酶（COX-2）或表皮生长因子受体（EGFR）信号通路的单独失活可能不足以治疗晚期胰腺癌（PC），这是最近临床试验的结果。3,3'-二吲哚甲烷（B-DIM）是 NF-κB 和 COX-2 的抑制剂，也是一种著名的化学预防剂。我们假设 B-DIM 同时抑制 NF-κB 和 COX-2，以及厄洛替尼抑制 EGFR，将增强细胞毒性药物吉西他滨的抗肿瘤作用，该药物已在体外和体内进行了测试。使用 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴盐（MTT）测定法评估单独或联合使用 B-DIM、厄洛替尼或吉西他滨治疗的七种 PC 细胞系中的存活细胞的抑制作用。在表达高水平 COX-2、EGFR 和 NF-κB 蛋白的 PC 细胞中观察到细胞活力显著抑制。观察到的抑制与 ELISA 评估的细胞凋亡增加有关。在 BxPC-3、COLO-357 和 HPAC 细胞中观察到 COX-2、NF-κB 和 EGFR 的表达明显下调，这表明同时靶向 EGFR、NF-κB 和 COX-2 比分别靶向信号通路更有效。我们的体外结果进一步得到体内研究的支持，表明 B-DIM 联合厄洛替尼和吉西他滨比单独使用这些药物更有效。基于我们的临床前体外和体内结果，我们得出结论，这种多靶向联合治疗可能被开发用于治疗肿瘤表达高水平 COX-2、EGFR 和 NF-κB 的 PC 患者。
