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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Design and Evaluation of S-Nitrosylated Human Serum Albumin as a Novel Anticancer Drug

Departments of Biopharmaceutics (N.K., H.K., T.K., M.O.) and Clinical Pharmaceutics (T.M.), Graduate School of Pharmaceutical Sciences, and Department of Cell Pathology (T.N., M.T.), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; and Pharmaceutical Research Center, Nipro Corporation, Shiga, Japan (N.K., K.N., K.U., J.-i.Y., N.Y., H.Y., T.K., M.S.)

In recent studies, the cytotoxic activity of NO has been investigated for its potential use in anticancer therapies. Nitrosated human serum albumin (NO-HSA) may act as a reservoir of NO in vivo. However, there are no published reports regarding the effects of NO-HSA on cancer. Therefore, the present study investigated the antitumor activity of NO-HSA. NO-HSA was prepared by incubating HSA, which had been sulfhydrylated using iminothiolane, with isopentyl nitrite (6.64 mol NO/mol HSA). Antitumor activity was examined in vitro using murine colon 26 carcinoma (C26) cells and in vivo using C26 tumor-bearing mice. Exposure to NO-HSA increased the production of reactive oxygen species in C26 cells. Flow cytometric analysis using rhodamine 123 showed that NO-HSA caused mitochondrial depolarization. Activation of caspase-3 and DNA fragmentation were observed in C26 cells after incubation with 100 µM NO-HSA for 24 h, and NO-HSA inhibited the growth of C26 cells in a concentration-dependent manner. The growth of C26 tumors in mice was significantly inhibited by administration of NO-HSA compared with saline and HSA treatment. Immunohistochemical analysis of tumor tissues demonstrated an increase in terminal deoxynucleotidyl transferase dUTP nickend labeling-positive cells in NO-HSA-treated mice, suggesting that inhibition of tumor growth by NO-HSA was mediated through induction of apoptosis. Biochemical parameters (such as serum creatinine, blood urea nitrogen, aspartate aminotransferase, and alanine aminotransferase) showed no significant differences among the three treatment groups, indicating that NO-HSA did not cause hepatic or renal damage. These results suggest that NO-HSA has the potential for chemopreventive and/or chemotherapeutic activity with few side effects.

Address correspondence to: Dr. Masaki Otagiri, Department of Biopharmaceutics, Graduate school of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan. E-mail: otagirim{at}gpo.kumamoto-u.ac.jp