title: Suppression of immune regulatory cells with combined therapy of celecoxib and sunitinib in renal cell carcinoma.
abstract: 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.
  
  
  CONCLUSIONS
  Combination therapy with sunitinib and celecoxib intensified the curative effects to renal cell carcinoma by suppressing immune regulatory cells.
authors.affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
authors.forename: Jianming
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
authors.forename: Guomin
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Immunology, Shanghai Medical College of Fudan University, Shanghai, 200032, China.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Chu
authors.affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Hu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology; D000068579:Celecoxib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects*; D009368:Neoplasm Transplantation; D011758:Pyrroles / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000096:biosynthesis; D000077210:Sunitinib; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D007211:Indoles; D011758:Pyrroles; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000068579:Celecoxib; D000077210:Sunitinib
keywords: cyclooxygenase-2 inhibitor; myeloid-derived suppressor cell; regulatory T cell; renal cell carcinoma; tyrosine kinase inhibitor