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¹ Division of Molecular and Clinical Microbiology, Department of Molecular Microbiology and Immunology, Second Department of Internal Medicine, and ² Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan, and ³ Division of Respiratory Diseases, Department of Medicine, Kawasaki Medical School, Kurashiki, Japan

Requests for reprints: Hiroshi Soda, Division of Molecular and Clinical Microbiology, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. Phone: 81-95-849-7273; Fax: 81-95-849-7285. E-mail: soda{at}net.nagasaki-u.ac.jp

Histone deacetylase inhibitors modulate the transcription of target genes and represent a new class of anticancer agents. The histone deacetylase inhibitor FR901228 has been reported to show antiproliferative and apoptotic effects in various malignancies including small cell lung cancer (SCLC) in vitro; however, the underlying mechanism is not fully understood. BCL-2 and BCL-XL are antiapoptotic proteins, of which overexpression has been reported to confer resistance to anticancer agents. High levels of BCL-2 and BCL-XL are frequently expressed in SCLC tumors. The present study was designed to clarify the apoptotic pathway of FR901228 in SCLC cells in vitro. FR901228 induced apoptosis in three SCLC cell lines after 24 hours of treatment. FR901228 activated caspase-9 and caspase-3 but not caspase-8, and the caspase-3 inhibitor Z-DEVD-fmk blocked the cytotoxicity of FR901228. FR901228 down-regulated the expression of bcl-2 and bcl-xL mRNA through de novo protein synthesis and suppressed the expression of BCL-2 and BCL-XL proteins. In addition, the combination of bcl-2 antisense oligonucleotides with FR901228 enhanced FR901228-induced caspase-3 activity and cytotoxicity. These findings suggest that FR901228 induces caspase-dependent apoptosis via the mitochondrial pathway rather than the death receptor pathway. Considering the possible contributions of BCL-2 and BCL-XL to multidrug resistance, FR901228 is a promising agent in the treatment of refractory as well as primary SCLC tumors.

Received 5/24/04; revised 7/26/04; accepted 8/27/04.

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