title: Additive effects of ulinastatin and docetaxel on growth of breast cancer xenograft in nude mice and expression of PGE2, IL-10, and IL-2 in primary breast cancer cells.
abstract: Ulinastatin is a broad-spectrum enzyme inhibitor extracted from urine. Previous data from our group suggested that ulinastatin could significantly inhibit proliferation of human breast MDA-MB-231 cells, growth of tumor xenograft in nude mice, and expression of interleukin (IL)-6 and IL-8. In the present study, we investigated whether there is an additive effect of ulinastatin and docetaxel on growth of breast cancer xenografts in nude mice and its possible mechanisms. Nude mice and primary human breast cancer cells were treated with phosphate buffered saline (PBS), ulinastatin, docetaxel, or ulinastatin plus docetaxel, respectively. Their effects on xenograft growth; expressions of cyclooxygenase-2 (COX2), prostaglandin E2 receptor 2 (EP2), IL-10, and IL-2; and secretion of prostaglandin E2 (PGE2) were examined using variety of methods, including semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), Western blot, enzyme-linked immunosorbent (ELISA) assay, and immunohistochemistry SP method. The treatment with ulinastatin, docetaxel, or ulinastatin plus docetaxel could significantly (1) inhibit COX2 and IL-10 expression in primary tumor cells at both mRNA and protein levels, (2) reduce PGE2 secretion in culture supernatant (p<0.05), (3) inhibit COX2, EP2, and IL-10 protein levels in primary xenograft of nude mice, and (4) increase IL-2 expression (p<0.05) in primary xenografts of nude mice. In addition, ulinastatin and docetaxel had additive effects. We suggest that ulinastatin had similar effects of docetaxel and can enhance docetaxel's anticancer effects possibly by inhibiting COX2 expression, reducing PGE2 and EP2 expression and their binding, upregulating IL-2, and downregulating IL-10.
authors.affiliation: Surgery Department of Breast and Thyroid, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Zhong
authors.forename: Hongyan
authors.initials: H
authors.lastname: Shen
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Sun
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D000077143:Docetaxel; D015536:Down-Regulation; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006023:Glycoproteins / Q000627:therapeutic use*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism; D043823:Taxoids / Q000627:therapeutic use*; D014361:Trypsin Inhibitors / Q000627:therapeutic use*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D006023:Glycoproteins; D007376:Interleukin-2; D012333:RNA, Messenger; D058307:Receptors, Prostaglandin E, EP2 Subtype; D043823:Taxoids; D014361:Trypsin Inhibitors; D016753:Interleukin-10; D000077143:Docetaxel; D051546:Cyclooxygenase 2; D015232:Dinoprostone; C028665:urinastatin