Piroxicam and cisplatin in a mouse model of peritoneal mesothelioma.
OBJECTIVE
The aim of the present study was to evaluate the effects of piroxicam, a widely used nonsteroidal anti-inflammatory drug, alone and in combination with cisplatin (CDDP), on cell growth of mesothelioma cells.


METHODS
Cell proliferation, cell cycle analysis, and microarray technology were done on MSTO-211H and NCI-H2452 cells treated with piroxicam. Moreover, the effects of piroxicam and CDDP on tumor growth and survival of mouse xenograft models of mesothelioma were determined.


RESULTS
Piroxicam treatment of MSTO-211H and NCI-H2452 cells resulted in a significant inhibition of proliferation. Cell cycle analysis revealed that there was an increase in the rate of apoptosis in MSTO-211H cells and an increase in the cells accumulating in G2-M in NCI-H2452. Moreover, a marked tumor growth inhibition and an extended survival of mice treated with a combination of piroxicam and CDDP in MSTO-211H cell-induced peritoneal mesotheliomas was observed. Last, GeneChip array analysis of MSTO-211H mesothelioma cell line revealed that piroxicam treatment caused up-regulation of metabolic pathway-associated genes and down-regulation of genes related to RNA processing apparatus. Of note, epidermal growth factor receptor, one of the new biological targets of chemotherapy for mesothelioma, was down-regulated and HtrA1, a serine protease recently shown to be an endogenous mediator of CDDP cytotoxicity, was up-regulated following piroxicam treatment both in vitro and in vivo.


CONCLUSIONS
These data suggest that piroxicam sensitizes mesothelioma cells to CDDP-induced cytotoxicity by modulating the expression of several target genes. Therefore, piroxicam in combination with CDDP might potentially be useful in the treatment of patients with mesothelioma.
Spugnini
Enrico P
EP
SAFU Department, CRS, Regina Elena Cancer Institute, Rome, Italy.
Cardillo
Irene
I
Verdina
Alessandra
A
Crispi
Stefania
S
Saviozzi
Silvia
S
Calogero
Raffaele
R
Nebbioso
Angela
A
Altucci
Lucia
L
Cortese
Giancarlo
G
Galati
Rossella
R
Chien
Jeremy
J
Shridhar
Viji
V
Vincenzi
Bruno
B
Citro
Gennaro
G
Cognetti
Francesco
F
Sacchi
Ada
A
Baldi
Alfonso
A
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010894:Piroxicam / Q000008:administration & dosage / Q000627:therapeutic use*
D010894:Piroxicam; D002945:Cisplatin