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Therapeutic Gene Delivery and Transfection in Human Pancreatic Cancer Cells using Epidermal Growth Factor Receptor-targeted Gelatin Nanoparticles
Published on: January 4, 2012
Simultaneous targeting of the epidermal growth factor receptor and cyclooxygenase-2 pathways for pancreatic cancer
Shadan Ali1, Basil F El-Rayes, Fazlul H Sarkar
1Department of Hematology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA.
Abstract:
The aims of this study were to determine the effects of (a) combining the epidermal growth factor receptor (EGFR) blocker (erlotinib) and the cyclooxygenase-2 inhibitor (celecoxib) on cell growth and apoptosis in human pancreatic cancer cell lines, (b) baseline EGFR expression on the potentiation of erlotinib-induced apoptosis by celecoxib, and (c) the effects of the combination on the expression of the COX-2, EGFR, HER-2/neu, and nuclear factor-kappaB (NF-kappaB). Baseline expression of EGFR was determined by Western blot analysis in five human pancreatic cancer cell lines. BxPC-3, PANC-1, and HPAC had high EGFR and MIAPaCa had low EGFR. Cells were grown in culture and treated with erlotinib (1 and 10 micromol/L), celecoxib (1 and 10 micromol/L), and the combination. Growth inhibition was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and apoptosis was assayed by ELISA. Reverse transcriptase-PCR was used to evaluate COX-2 and EGFR mRNA. EGFR, COX-2, and HER-2/neu expression was determined by Western immunoblotting. Electrophoretic mobility shift assay was used to evaluate NF-kappaB activation. Growth inhibition and apoptosis were significantly (P < 0.05) higher in BxPC-3, HPAC, and PANC-1 cells treated with celecoxib and erlotinib than cells treated with either celecoxib or erlotinib. However, no potentiation in growth inhibition or apoptosis was observed in the MIAPaCa cell line with low expression of the EGFR. Significant down-regulation of COX-2 and EGFR expression was observed in the BxPC-3 and HPAC cells treated with the combination of erlotinib (1 micromol/L) and celecoxib (10 micromol/L) compared with celecoxib- or erlotinib-treated cells. Celecoxib significantly down-regulated HER-2/neu expression in BxPC-3 and HPAC cell lines. Significant inhibition of NF-kappaB activation was observed in BxPC-3 and HPAC cell lines treated with erlotinib and celecoxib. (a) Celecoxib can potentiate erlotinib-induced growth inhibition and apoptosis in pancreatic cell lines, (b) high baseline EGFR expression is a predictor of this potentiation, and (c) the down-regulation of EGFR, COX-2, and HER-2/neu expression and NF-kappaB inactivation contributes to the potentiation of erlotinib by celecoxib.
Insights
Combining celecoxib with erlotinib enhances pancreatic cancer cell growth inhibition and apoptosis, particularly in cells with high epidermal growth factor receptor (EGFR) expression. This potentiation involves down-regulation of EGFR, COX-2, HER-2/neu, and NF-kappaB.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Pancreatic cancer remains a significant health challenge with limited effective treatments.
- Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are implicated in pancreatic cancer progression.
- Targeting these pathways individually has shown some efficacy, but combination strategies require further investigation.
Purpose of the Study:
- To investigate the combined effects of erlotinib (EGFR inhibitor) and celecoxib (COX-2 inhibitor) on pancreatic cancer cell growth and apoptosis.
- To determine if baseline EGFR expression influences the potentiation of erlotinib-induced apoptosis by celecoxib.
- To assess the impact of the combination therapy on the expression of key molecular targets including COX-2, EGFR, HER-2/neu, and nuclear factor-kappaB (NF-kappaB).
Main Methods:
- Utilized five human pancreatic cancer cell lines with varying baseline EGFR expression.
- Assessed cell growth inhibition using the MTT assay and apoptosis via ELISA.
- Analyzed the expression of COX-2, EGFR, HER-2/neu, and NF-kappaB activation using RT-PCR, Western immunoblotting, and electrophoretic mobility shift assay.
Main Results:
- The combination of erlotinib and celecoxib significantly enhanced growth inhibition and apoptosis in pancreatic cancer cell lines with high EGFR expression (BxPC-3, PANC-1, HPAC).
- No potentiation was observed in cell lines with low EGFR expression (MIAPaCa).
- Combination treatment led to significant down-regulation of COX-2, EGFR, and HER-2/neu expression, and inhibited NF-kappaB activation in responsive cell lines.
Conclusions:
- Celecoxib potentiates erlotinib-induced anti-cancer effects in pancreatic cancer cells.
- High baseline EGFR expression is a predictive marker for response to this combination therapy.
- The observed potentiation is attributed to the down-regulation of EGFR, COX-2, HER-2/neu, and inactivation of NF-kappaB.
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