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

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.

• Authors: Shadan Ali, Sanjeev Banerjee, Jacqueline M Schaffert, Bassel F El-Rayes, Philip A Philip, Fazlul H Sarkar
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 110 Issue 1 Pg. 171-81 (May 2010) ISSN: 1097-4644 [Electronic] United States
• PMID: 20213764 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Retracted Publication)
• Copyright: (c) 2010 Wiley-Liss, Inc.

Chemical References

• Antineoplastic Agents
• Cyclooxygenase Inhibitors
• Indoles
• NF-kappa B
• Quinazolines
• Deoxycytidine
• Erlotinib Hydrochloride
• Cyclooxygenase 2
• PTGS2 protein, human
• ErbB Receptors
• 3,3'-diindolylmethane
• Gemcitabine

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase Inhibitors (pharmacology)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Disease Models, Animal
• Drug Synergism
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Erlotinib Hydrochloride
• Female
• Humans
• Indoles (pharmacology)
• Mice
• Mice, SCID
• NF-kappa B (antagonists & inhibitors, metabolism)
• Pancreatic Neoplasms (drug therapy, enzymology, pathology)
• Quinazolines (pharmacology)
• Signal Transduction (drug effects)
• Treatment Outcome
• Tumor Stem Cell Assay
• Xenograft Model Antitumor Assays
• Gemcitabine