Piroxicam and Cisplatin in a Mouse Model of Peritoneal Mesothelioma
Thursday, October 26th, 2006.
Clinical Cancer Research. Vol. 12, 6133-6143, October 15, 2006. [Link]
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.
Glossary
- oncology
- (on-call-o-jee) the branch of medicine concerned with the diagnosis and treatment of cancer.
- gene
- a segment of DNA that contains information on hereditary characteristics such as hair color, eye color, and height, as well as susceptibility to certain diseases. Women who have BRCA1 or BRCA2 gene mutations (defects) have an inherited tendency to develop breast cancer.
- chemotherapy
- (key-mo-THER-uh-pee) treatment with drugs to destroy cancer cells. Chemotherapy is often used with surgery or radiation to treat cancer when the cancer has spread, when it has come back (recurred), or when there is a strong chance that it could recur.
- cell
- the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.
- cancer
- malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.
- tumor
- an abnormal lump or mass of tissue. Tumors can be benign (not cancerous) or malignant (cancerous).
- mesothelioma
- a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.
- peritoneal
- (pair-uh-tuh-nee-al) the serous membrane that lines the cavity of the abdomen. (More on Peritoneal Mesothelioma.)
- apoptosis
- a type of cell death in which the cell basically commits suicide; scientists believe some types of cancer may originate from an interruption of this programmed cell death, allowing cells to grow out of control.
- epidermal growth factor receptor
- The process of cell division, growth, differentiation and death is a highly regulated process. Several class of trans membrane receptors play a pivot role in this process, of these, epidermal growth factor receptor (EGFR) a member of Receptor Tyrosine Kinase (RTK) family are best known. These comprises of four receptors Erb B1/HER 1, Erb B2 / HER 2, Erb B3/ HER 3, and Erb B4 / HER 4. Of these HER 2 is the most favoured target. (Source: Manoj Pandey and K Chandramohan)
