Chronic anti-inflammatory drug therapy inhibits gel-forming mucin production in a murine xenograft model of human pseudomyxoma peritonei.
BACKGROUND
Intraperitoneal accumulation of mucinous ascites in pseudomyxoma peritonei (PMP) promotes an inflammatory/fibrotic reaction that progresses to bowel obstruction and eventual patient demise. Cytokines and inflammation-associated transcription factor binding sites, such as glucocorticoid response elements and COX-2, regulate secretory mucin, specifically MUC2, production. We hypothesized that anti-inflammatory drugs targeting inflammation-associated pathways may reduce mucin production and subsequent disease morbidity in PMP.


METHODS
The effects of dexamethasone and Celebrex were assessed in mucin-secreting human colon cancer LS174T cells in vitro and murine xenograft models of LS174T and human appendiceal PMP in vivo by serial parametric measurements, MUC2 transcripts via real-time RT-PCR, and MUC2 protein expression via immunofluorescence assays.


RESULTS
Dexamethasone significantly inhibited basal MUC2 mRNA levels in LS174T cells, inhibited mucinous tumor accumulation in an intraperitoneal PMP xenograft model, and prolonged survival in a subcutaneous LS174T xenograft model. Celebrex significantly inhibited sodium butyrate-stimulated MUC2 mRNA levels in LS174T cells and demonstrated a statistically nonsignificant trend toward reduced mucinous tumor growth and prolonged survival in the xenograft models. MUC2 protein analysis by immunofluorescence demonstrated a dual effect of dexamethasone on mucin production and tumor cell count.


CONCLUSIONS
Inflammatory mediators are known to regulate mucin production and may promote overexpression of MUC2 by neoplastic cells with goblet cell phenotype in PMP. Anti-inflammatory drugs, dexamethasone and Celebrex, could inhibit extracellular mucin production in PMP by targeting inflammatory cascades and, therefore, may decrease compressive symptoms, increase the disease-free interval, and reduce the extent or frequency of morbid cytoreductive surgeries.
Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. choudrymh@upmc.edu
Haroon Asif
HA
Choudry
Arun
A
Mavanur
Mark E
ME
O'Malley
Herbert J
HJ
Zeh
Z  Sheng
Z
Guo
David L
DL
Bartlett
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D001063:Appendiceal Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000068579:Celecoxib; D003110:Colonic Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003907:Dexamethasone / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D055262:Mucin-2 / Q000096:biosynthesis* / Q000187:drug effects / Q000302:isolation & purification; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D010534:Peritoneal Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011553:Pseudomyxoma Peritonei / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011720:Pyrazoles / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000893:Anti-Inflammatory Agents; C524625:MUC2 protein, human; D055262:Mucin-2; D011720:Pyrazoles; D013449:Sulfonamides; D003907:Dexamethasone; D000068579:Celecoxib