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Takao Matsubara,
Katsuyuki Kusuzaki,
Akihiko Matsumine,
Hiroaki Murata,
Haruhiko Satonaka,
Ken Shintani,
Tomoki Nakamura,
Hajime Hosoi,
Tomoko Iehara, Toru Sugimoto,
Atsumasa Uchida
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ABSTRACT: Rhabdomyosarcoma is a common malignant soft tissue that frequently involves bone and major neurovascular structures and resection of deep-seated rhabdomyosarcoma can cause severe dysfunction in the affected limbs. Based on the mouse osteosarcoma model, we developed a new surgical approach involving photodynamic surgery (PDS), photodynamic therapy (PDT) and radiodynamic therapy (RDT) using acridine orange (AO). Six rhabdomyosarcoma cases were treated using this new modality after confirming the effectiveness of AO-PDT on human rhabdomyosarcoma cell lines. All patients had almost normal limb function after surgery, with only one recurrence. Based on these results, AO-PDS, PDT and RDT can be used to preserve excellent limb function in patients with rhabdomyosarcoma involving major nerves and vessels or bones.
Oncology Reports 02/2009; 21(1):89-94. · 1.84 Impact Factor
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Motonobu Watanabe,
Souichi Adachi,
Hiroshi Matsubara,
Tsuyoshi Imai,
Yoshihiro Yui,
Yasuhiro Mizushima,
Yoshimi Hiraumi,
Ken-ichiro Watanabe,
Yuri Kamitsuji,
Shin-ya Toyokuni,
Hajime Hosoi, Toru Sugimoto,
Junya Toguchida,
Tatsutoshi Nakahata
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ABSTRACT: Malignant rhabdoid tumors (MRT) exhibit a very poor prognosis because of their resistance to chemotherapeutic agents and new therapies are needed for the treatment of this cancer. Here, we show that the histone deacetylase (HDAC) inhibitor FK228 (depsipeptide) has an antitumor effect on MRT cells both in vitro and in vivo. FK228 is a unique cyclic peptide and is among the most potent inhibitors of both Class I and Class II HDACs. FK228 inhibited proliferation and induced apoptosis in all MRT cell lines tested. Preincubation with the pancaspase inhibitor zVAD-fmk did not completely rescue FK228-induced cell death, although it did inhibit apoptosis. Transmission electron microscopy (TEM) showed that FK228 could stimulate MRT cells to undergo apoptosis, necrosis or autophagy. FK228 converted unconjugated microtubule-associated protein light chain 3 (LC3-I) to conjugated light chain 3 (LC3-II) and induced localization of LC3 to autophagosomes. Apoptosis inducing factor (AIF), which plays a role in caspase-independent cell death, translocated to the nucleus in response to FK228 treatment. Moreover, small interfering RNA (siRNA) targeting of AIF prevented the morphological changes associated with autophagy and redistribution of LC3 to autophagosomes. Disrupting autophagy with chloroquine treatment enhanced FK228-induced cell death. In vivo, FK228 caused a reduction in tumor size and induced autophagy in tumor tissues. Using immunoelectron microscopy, we confirmed AIF translocation into the nucleus of FK228-induced autophagic cells in vivo. Thus, FK228 is a novel candidate for an antitumor agent for MRT cells.
International Journal of Cancer 10/2008; 124(1):55-67. · 5.44 Impact Factor
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ABSTRACT: N-Methyl-D-aspartate-mediated neurotoxicity is known to involve nitric oxide production and to be augmented in an environment of reactive oxygen species. We used TUNEL staining and homogenous cytosolic immunoreactivity of cytochrome c in an acute brain slice preparation to investigate the influence of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, on N-methyl-D-aspartate-induced apoptosis. Cerebrocortical slices were obtained from parietal lobes of 7-day-old Sprague-Dawley rats, superfused with well-oxygenated artificial cerebrospinal fluid, and metabolically recovered. Subsequent 30-min exposures to 10 microM N-methyl-D-aspartate in treated and untreated slices were followed by 4 h of recovery superfusion with oxygenated artificial cerebrospinal fluid. Outcomes were compared for three groups of slices: "the N-methyl-D-aspartate-only group"; "the edaravone treatment group", which had 20 microM edaravone present throughout and subsequent to N-methyl-D-aspartate exposure; the "control group", in which slices were superfused only with oxygenated artificial cerebrospinal fluid. At the conclusion of recovery (t = 4 h), the percentage of TUNEL-positive cells in the edaravone treatment group (7.0+/-3.3%) was significantly reduced from the percentage for the N-methyl-D-aspartate-only group (21.9+/-4.1%), and insignificantly greater than the percentage for the control group (3.4+/-2.1%). Percentages of cytochrome c positive cells at t = 1 h were significantly increased (p < 0.01) in the N-methyl-d-aspartate-only group (30.6+/-1.9%) compared to percentages for both the control group (11.4+/-2.6%) and the edaravone treatment group (15.2+/-2.1%). Edaravone's reduction in TUNEL staining and cytochrome c release provides evidence of reactive oxygen species mechanisms and antioxidant benefits in cytochrome c-mediated apoptosis during N-methyl-D-aspartate excitotoxicity.
International Journal of Developmental Neuroscience 10/2006; 24(6):349-56. · 2.42 Impact Factor
