Clinical Cancer Research. Vol. 12, 6133-6143, October 15, 2006. [Link]

Enrico P. Spugnini1, Irene Cardillo2, Alessandra Verdina2, Stefania Crispi5, Silvia Saviozzi8, Raffaele Calogero8, Angela Nebbioso6, Lucia Altucci6, Giancarlo Cortese1, Rossella Galati2, Jeremy Chien9, Viji Shridhar9, Bruno Vincenzi3, Gennaro Citro1, Francesco Cognetti4, Ada Sacchi2 and Alfonso Baldi7

Authors’ Affiliations: 1 SAFU Department, CRS and 2 Laboratory D, Department for the Development of Therapeutic Programs, CRS, Regina Elena Cancer Institute; 3 Section of Oncology, Campus BioMedico University; 4 Division of Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy; 5 Gene Expression Core-Human Molecular Genetics Laboratory, Institute of Genetics and Biophysics, Consiglio Nazionale delle Ricerche, Naples, Italy; 6 Department of General Pathology and Oncology, “Centro Sperimentale S. Andrea delle Dame”; 7 Section of Pathology, Department of Biochemistry and Biophysics, Second University of Naples, Naples, Italy; 8 Department of Clinical and Biological Science, University of Turin, Turin, Italy; and 9 Department of Laboratory Medicine and Experimental Pathology, Mayo Clinic Cancer Center, Rochester, Minnesota

Requests for reprints: Alfonso Baldi, Section of Pathology, Department of Biochemistry, II University of Naples, Via L. Armanni, 5, 80138 Naples, Italy. Phone: 39-815-666003; Fax: 39-815-569693; E-mail: alfonsobaldi@tiscali.it

Abstract

Purpose: 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.

Experimental Design: 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.

Conclusion: 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.