Celecoxib enhances the efficacy of 15-hydroxyprostaglandin dehydrogenase gene therapy in treating murine breast cancer.

Abstract

PURPOSE:

The overexpression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) has been proved to inhibit tumor growth and metastasis through degradation of prostaglandin E2 (PGE2), which is often overexpressed in various cancers and accelerates tumor progression. Cyclooxygenase-2 (COX-2), a synthase of PGE2, actively produces much PGE2 to counteract the 15-PGDH-induced antitumor efficacy. Here, we investigated the combinational effect by using pcDNA3.1(+) encoding mouse 15-PGDH gene therapy and celecoxib, a COX-2 inhibitor, in mouse breast cancers.

METHODS:

Mice bearing 4T1 were treated with short-term administration of the COX-2 inhibitor celecoxib (40 mg/kg/day) plus liposome-encapsulated mouse 15-PGDH in order to determine their synergistic antitumor activity in vivo. And the possible mechanisms were investigated.

RESULTS:

We observed that the combination treatment of 15-PGDH and celecoxib significantly inhibited tumor growth and lung metastases than monotherapy or controls. Moreover, the effect of combination treatment was associated with significant reduction of PGE2 in serum, which resulted from increased 15-PDGH and decreased COX-2 in tumor tissues. The tumor tissues in combination treatment presented more apoptotic cells and less microvessel density. Notably, the number of myeloid-derived suppressor cells in the spleen was also significantly decreased in the combination treatment than others.

CONCLUSIONS:

Our findings suggested that celecoxib increased the antitumor activity of 15-PGDH by synergistically blocking PGE2 pathway, which might be a new feasible way for cancer therapy.

• Authors: Binglan Zhang, Xuelei Ma, Zhimian Li, Xiang Gao, Fengtian Wang, Lei Liu, Guobo Shen, Yaxiong Sang, Minmin Li, Yuli Li, Jingyi Zhao, Yuquan Wei
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 139 Issue 5 Pg. 797-807 (May 2013) ISSN: 1432-1335 [Electronic] Germany
• PMID: 23385883 (Publication Type: Journal Article)

Chemical References

• Cyclooxygenase 2 Inhibitors
• Pyrazoles
• Sulfonamides
• Hydroxyprostaglandin Dehydrogenases
• 15-hydroxyprostaglandin dehydrogenase
• Cyclooxygenase 2
• Celecoxib
• Dinoprostone

Topics

• Animals
• Apoptosis (drug effects, genetics)
• Celecoxib
• Cell Line, Tumor
• Combined Modality Therapy
• Cyclooxygenase 2 (genetics, metabolism)
• Cyclooxygenase 2 Inhibitors (administration & dosage, adverse effects)
• Dinoprostone (metabolism)
• Disease Models, Animal
• Female
• Genetic Therapy (adverse effects)
• Humans
• Hydroxyprostaglandin Dehydrogenases (genetics, metabolism)
• Lung Neoplasms (pathology, secondary)
• Mammary Neoplasms, Experimental (genetics, immunology, pathology, therapy)
• Mice
• Myeloid Cells (immunology, metabolism)
• Neovascularization, Pathologic (drug therapy, genetics)
• Pyrazoles (administration & dosage, adverse effects)
• Spleen (immunology, pathology)
• Sulfonamides (administration & dosage, adverse effects)
• Tumor Burden (drug effects, genetics)