Piroxicam and Cisplatin in a Mouse Model of Peritoneal Mesothelioma

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.