Targeting cyclooxygenase 2 and HER-2/neu pathways inhibits colorectal carcinoma growth.
OBJECTIVE
The cyclooxygenase 2 (COX-2) and ErbB/HER pathways are important modulators of cancer cell growth. We sought to determine the effects of treatment with a specific COX-2 inhibitor and/or a monoclonal antibody against the ErbB receptor subtype HER-2/neu on carcinoma cell growth.


METHODS
A cell-proliferation assay was used to determine the response of HCA-7 cells to the HER-3/HER-4 ligand heregulin beta-1 (HRGbeta-1). Both in vitro and in vivo assays were used to determine the effects of the selective COX-2 inhibitor, celecoxib, and/or an anti-HER-2/neu monoclonal antibody (either Herceptin [Genetech Inc., S. San Francisco, CA] or 2C4) on cell growth.


RESULTS
HCA-7 cells express HER-2/neu messenger RNA and protein, and exposure of these cells to HRGbeta-1 results in a significant stimulation of cell growth. Celecoxib or Herceptin inhibits HCA-7 cell growth in vitro and in vivo. Combination therapy with celecoxib plus Herceptin or celecoxib plus 2C4 resulted in additive effects that resulted in almost complete inhibition of tumor growth.


CONCLUSIONS
Combined treatment with COX-2 and HER-2/neu inhibitors more effectively reduces colorectal carcinoma growth than either agent alone. Therefore, targeting of both the COX-2 and ErbB signaling pathways may represent a novel approach for the treatment and/or prevention of colorectal cancer in humans.
Mann
M
M
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2279, USA.
Sheng
H
H
Shao
J
J
Williams
C S
CS
Pisacane
P I
PI
Sliwkowski
M X
MX
DuBois
R N
RN
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068579:Celecoxib; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000502:physiology; D008565:Membrane Proteins; D051379:Mice; D009368:Neoplasm Transplantation; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D011720:Pyrazoles; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D013449:Sulfonamides / Q000008:administration & dosage*; D014183:Transplantation, Heterologous; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D018719:Erb-b2 Receptor Tyrosine Kinases; D013449:Sulfonamides; D000068878:Trastuzumab; C496540:PTGS2 protein, human