Chemotherapeutic agents sensitize sarcoma cell lines to tumor necrosis factor-related apoptosis-inducing ligand-induced caspase-8 activation, apoptosis and loss of mitochondrial membrane potential
Takahito Hotta
Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Department of Orthopedic Surgery, Tokyo Medical University Hospital, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
Search for more papers by this authorHidekazu Suzuki
Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Department of Orthopedic Surgery, Tokyo Medical University Hospital, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
Search for more papers by this authorShuzou Nagai
Department of Orthopedic Surgery, Tokyo Medical University Hospital, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
Search for more papers by this authorKengo Yamamoto
Department of Orthopedic Surgery, Tokyo Medical University Hospital, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
Search for more papers by this authorAtsuhiro Imakiire
Department of Orthopedic Surgery, Tokyo Medical University Hospital, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
Search for more papers by this authorEiko Takada
Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Intractable Disease Research Center, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Search for more papers by this authorMizue Itoh
Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Search for more papers by this authorCorresponding Author
Junichiro Mizuguchi
Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Intractable Disease Research Center, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Intractable Disease Research Center, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan. Tel.: +81-3-3351-6141; fax: +81-3-3341-2941Search for more papers by this authorTakahito Hotta
Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Department of Orthopedic Surgery, Tokyo Medical University Hospital, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
Search for more papers by this authorHidekazu Suzuki
Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Department of Orthopedic Surgery, Tokyo Medical University Hospital, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
Search for more papers by this authorShuzou Nagai
Department of Orthopedic Surgery, Tokyo Medical University Hospital, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
Search for more papers by this authorKengo Yamamoto
Department of Orthopedic Surgery, Tokyo Medical University Hospital, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
Search for more papers by this authorAtsuhiro Imakiire
Department of Orthopedic Surgery, Tokyo Medical University Hospital, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
Search for more papers by this authorEiko Takada
Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Intractable Disease Research Center, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Search for more papers by this authorMizue Itoh
Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Search for more papers by this authorCorresponding Author
Junichiro Mizuguchi
Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Intractable Disease Research Center, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Intractable Disease Research Center, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan. Tel.: +81-3-3351-6141; fax: +81-3-3341-2941Search for more papers by this authorAbstract
Chemotherapeutic agents have been used for the treatment of patients with osteosarcoma (OS). However, inherent or acquired resistance to these agents is a serious problem in the management of OS patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered to induce apoptosis in a variety of cancer cells but not normal cells. In the present study, we examined whether chemotherapeutic agents enhance TRAIL-induced apoptosis in the sarcoma cell lines MG-63 and SaOS-2. Pretreatment with sub-toxic or slightly toxic concentrations of chemotherapeutic agents (cis-diammine dichloroplatinum, CDDP and doxorubicin, DXR) sensitized both cell lines to TRAIL-induced apoptosis, as assessed by the propidium iodide or Annexin V-Cy5 staining method. These cell lines expressed death receptors TRAIL-receptor 1 (TRAIL-R1) and TRAIL-R2, which were unaltered by treatment with CDDP, as assessed by flow cytometry. The decoy receptors TRAIL-R3 and -R4 were barely detected in both cell lines. CDDP down-regulated c-FLIP, tending to lower the activation threshold required for TRAIL-induced caspase-8 activation. The CDDP-pretreated cells indeed demonstrated more increased TRAIL-mediated caspase-8 activation, loss of mitochondrial membrane potential (ΔΨm), and apoptosis than untreated cells. Consequently, the activated caspase-8 might lead to either activation of effector caspases such as caspase-3 or loss in ΔΨm. Both the increased caspase activation and mitochondrial dysfunction induced by combination of CDDP and TRAIL would contribute to enhanced apoptotic cell death. The results of the present study would be valuable for the design of novel treatment modalities for patients with OS. © 2003 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.
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