Suppression of immune regulatory cells with combined therapy of celecoxib and sunitinib in renal cell carcinoma.
OBJECTIVE
To observe the the potential benefit of sunitinib in combination with cyclooxygenase-2(COX-2) inhibitor in renal cell carcinoma therapy.


METHODS
769-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.


RESULTS
769-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.


CONCLUSION
Combination therapy with sunitinib and celecoxib intensified the curative effects to renal cell carcinoma by suppressing immune regulatory cells.
['Zhao|Qi|Q|', 'Guo|Jianming|J|', 'Wang|Guomin|G|', 'Chu|Yiwei|Y|', 'Hu|Xiaoyi|X|']
D000818:Animals D000970:Antineoplastic Agents D000971:Antineoplastic Combined Chemotherapy Protocols D002292:Carcinoma, Renal Cell D000068579:Celecoxib D045744:Cell Line, Tumor D049109:Cell Proliferation D052246:Cyclooxygenase 2 Inhibitors D016178:Granulocyte-Macrophage Colony-Stimulating Factor D006801:Humans D007211:Indoles D007680:Kidney Neoplasms D018655:Lymphocyte Count D051379:Mice D008807:Mice, Inbred BALB C D000072737:Myeloid-Derived Suppressor Cells D009368:Neoplasm Transplantation D011758:Pyrroles D050796:STAT3 Transcription Factor D000077210:Sunitinib D050378:T-Lymphocytes, Regulatory
renal cell carcinoma myeloid-derived suppressor cell regulatory T cell cyclooxygenase-2 inhibitor tyrosine kinase inhibitor