Effect of combined cyclooxygenase-2 and matrix metalloproteinase inhibition on human sarcoma xenografts
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Updated: Aug 11, 2026
Three-Dimensional Bone Extracellular Matrix Model for Osteosarcoma
Published on: April 12, 2019
David S Dickens1, Timothy P Cripe
1Division of Pediatric Hematology/Oncology, Cincinnati Children's Hospital Medical Center, Ohio 45229, USA.
Purpose:
Sarcomas express cyclooxygenase (COX)-2, an inducible enzyme with known tumor-promoting activity. COX-2 inhibition is efficacious against many cancer types but has not been tested for human sarcomas. Matrix metalloproteinase (MMP) inhibitors also possess antiproliferative activity. Because MMP inhibitor therapy induces COX-2 expression, the authors hypothesized that the combination of COX-2 and MMP inhibitors results in a synergistic antitumor effect.
Methods:
Human osteosarcoma or rhabdomyosarcoma cells were injected into athymic mice. Tumor development and growth were measured following treatment with a COX-2 inhibitor (celecoxib), an MMP inhibitor (doxycycline), or both. The tumors were analyzed for necrosis, apoptosis, cyclooxygenase activity (PGE2 production), and MMP-2 levels.
Results:
When treatment was started prior to tumor cell implantation, doxycycline inhibited osteosarcoma tumor growth alone and in combination with celecoxib (30% and 33% reduction, respectively). An effect on osteosarcoma tumor implantation rates was noted in mice receiving doxycycline alone and in combination with celecoxib (12.5% and 6.25% reduction, respectively). Established osteosarcoma and rhabdomyosarcoma tumors were inhibited only by combination therapy (36% and 55%, respectively). A higher proportion of osteosarcoma tumors in the combination therapy group had more than 50% necrosis (3/7) when compared with control tumors (0/8). Antitumor effects did not correlate with PGE2 levels, suggesting the observed interaction with doxycycline was due to previously described non-enzymatic effects of celecoxib.
Conclusions:
The authors' preclinical data suggest that the combination of inexpensive, nontoxic, oral COX-2 and MMP inhibitors may be useful for the treatment of some types of solid tumors.
Insights
Combining cyclooxygenase-2 (COX-2) and matrix metalloproteinase (MMP) inhibitors shows promise for treating sarcomas. This preclinical study found that combined COX-2 and MMP inhibition effectively reduced tumor growth and increased necrosis in mice.
Area of Science:
- Oncology
- Pharmacology
Background:
- Sarcomas express cyclooxygenase-2 (COX-2), an enzyme implicated in tumor promotion.
- COX-2 inhibitors are effective against various cancers, but their efficacy in human sarcomas is untested.
- Matrix metalloproteinase (MMP) inhibitors have antiproliferative effects, and their therapy can increase COX-2 expression.
Purpose of the Study:
- To investigate the synergistic antitumor effect of combining COX-2 and MMP inhibitors.
- To evaluate the efficacy of celecoxib (COX-2 inhibitor) and doxycycline (MMP inhibitor) in preclinical sarcoma models.
Main Methods:
- Human osteosarcoma and rhabdomyosarcoma cells were implanted into athymic mice.
- Tumor growth was monitored after treatment with celecoxib, doxycycline, or both.
- Tumors were analyzed for necrosis, apoptosis, cyclooxygenase activity (PGE2 production), and MMP-2 levels.
Main Results:
- Combination therapy significantly inhibited established osteosarcoma (36%) and rhabdomyosarcoma (55%) tumors.
- Doxycycline alone inhibited osteosarcoma growth (30%) when initiated before implantation.
- Combination therapy led to increased necrosis in osteosarcoma tumors compared to controls.
Conclusions:
- Preclinical data suggest that combining COX-2 and MMP inhibitors may offer a viable treatment strategy for certain solid tumors.
- The combination of inexpensive, non-toxic, oral agents warrants further investigation for sarcoma treatment.
