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J Cell Biochem. 2010 May;110(1):171-81. doi: 10.1002/jcb.22523.

Concurrent inhibition of NF-kappaB, cyclooxygenase-2, and epidermal growth factor receptor leads to greater anti-tumor activity in pancreatic cancer.

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  • 1Division of Hematology/Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA.

Abstract

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.

(c) 2010 Wiley-Liss, Inc.

PMID:
20213764
[PubMed - indexed for MEDLINE]
PMCID:
PMC3093967
Free PMC Article

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