Abstract
ObjectiveTo observe the the potential benefit of sunitinib in combination with cyclooxygenase-2(COX-2) inhibitor in renal cell carcinoma therapy.Methods769-p cell lines were treated with sunitinib, celecoxib, or in combination at different concentrations respectively. We investigated the expression of granulocyte-macrophage colony stimulating factor (GM-CSF) in 769-p and cell proliferation in vitro. BALB/c mice implanted with Renca cells were divided into 4 groups and administered orally by gavage with sunitinib, COX-2 inhibitor (celecoxib) monotherapy or combination, and PBS respectively. Tumor growth and animal survival were observed. The myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in peripheral blood and spleen were determined by flow cytometry. The MDSCs protein was extracted for STAT3 analysis by western blot.Results769-p cell lines were suppressed in a dose and time-dependent manner. The expression of GM-CSF was substantially inhibited by celecoxib and sunitinib. Combination of sunitinib and celecoxib in vivo could effectively reduce the MDSCs than those in control group. Meanwhile, the CD4+ lymphocytes were strongly increased and the expression of signal transducer and activator of transcription 3 (STAT3) in MDSCs were significantly reduced.ConclusionCombination therapy with sunitinib and celecoxib intensified the curative effects to renal cell carcinoma by suppressing immune regulatory cells.
Highlights
In recent years, the application of targeted therapy of VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI) are gradually replacing the conventional immunotherapy and become a standard option in the treatment of metastatic renal cell carcinoma
Combination therapy with sunitinib and celecoxib intensified the curative effects to renal cell carcinoma by suppressing immune regulatory cells
Renal carcinoma cells were discovered to express a high level of endogenous granulocyte-macrophage colonystimulating factor (GM-CSF)
Summary
The application of targeted therapy of VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI) are gradually replacing the conventional immunotherapy and become a standard option in the treatment of metastatic renal cell carcinoma (mRCC). Several investigations showed that a novel anti-inflammation medicine, COX-2 inhibitor, disclosed potent anti-tumor activity in certain murine tumor models by extending the effectiveness of VEGFR inhibition in human renal cell carcinoma xenografts [1]. The process of tumor angiogenesis may be affected by the inhibition of VEGF/VEGFR signaling pathway, as well as the stimulation of anti-tumor immune responses [2, 3]. Tumor growth is always associated with impaired antitumor immune responses, while VEGF/VEGFR are essential for tumorinduced angiogenesis and tumor growth. VEGF/ VEGFR maybe play important roles in tumor-associated immunosuppression [4]
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