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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
Author(s) -
Hotta Takahito,
Suzuki Hidekazu,
Nagai Shuzou,
Yamamoto Kengo,
Imakiire Atsuhiro,
Takada Eiko,
Itoh Mizue,
Mizuguchi Junichiro
Publication year - 2003
Publication title -
journal of orthopaedic research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.041
H-Index - 155
eISSN - 1554-527X
pISSN - 0736-0266
DOI - 10.1016/s0736-0266(03)00062-7
Subject(s) - propidium iodide , apoptosis , cancer research , programmed cell death , tumor necrosis factor alpha , annexin , caspase 8 , caspase , cell culture , caspase 3 , biology , chemistry , microbiology and biotechnology , immunology , biochemistry , genetics
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 (ΔΨ m ), 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 ΔΨ m . 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.