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Blood, 1 September 2007, Vol. 110, No. 5, pp. 1664-1674. Prepublished online as a Blood First Edition Paper on June 5, 2007; DOI 10.1182/blood-2007-01-068981. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-01-068981v1 110/5/1664    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hasegawa, H. Articles by Kamihira, S. Search for Related Content PubMed PubMed Citation Articles by Hasegawa, H. Articles by Kamihira, S. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA A novel natural compound, a cycloanthranilylproline derivative (Fuligocandin B), sensitizes leukemia cells to apoptosis induced by tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) through 15-deoxy-12, 14 prostaglandin J2 production Hiroo Hasegawa1,6, Yasuaki Yamada1, Kanki Komiyama2, Masahiko Hayashi3, Masami Ishibashi4, Toshiaki Sunazuka2,3, Takeshi Izuhara5, Kazuyuki Sugahara1, Kazuto Tsuruda1, Masato Masuda6, Nobuyuki Takasu6, Kunihiro Tsukasaki7, Masao Tomonaga7, and Shimeru Kamihira1 1 Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki; 2 Kitasato Institute, Tokyo; 3 Kitasato Institute for Life Sciences, Kitasato University, Tokyo; 4 Graduate School of Pharmaceutical Sciences, Chiba University, Chiba; 5 School of Pharmaceutical Sciences, Kitasato University, Tokyo; 6 Second Department of Internal Medicine, University of the Ryukyus, Okinawa; and 7 Department of Hematology, Atomic Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) induces apoptosis in many transformed cells; however, not all human tumors respond to TRAIL, potentially limiting its therapeutic utility. Although there is substantial evidence that cytotoxic drugs can augment sensitivity to TRAIL, it has become important to know what kinds of nontoxic drugs can be used together with TRAIL. We thus screened several natural compounds that can overcome resistance to TRAIL and found that a cycloanthranilylproline derivative, Fuligocandin B (FCB), an extract of myxomycete Fuligo candida, exhibited significant synergism with TRAIL. Treatment of the TRAIL-resistant cell line KOB with FCB and TRAIL resulted in apparent apoptosis, which was not induced by either agent alone. FCB increased the production of 15-deoxy-12,14 prostaglandin J2 (15d-PGJ2), an endogenous PPAR ligand, through activation of cyclooxygenase-2 (COX-2). This unique mechanism highlighted the fact that 15d-PGJ2 directly enhanced sensitivity to TRAIL by inhibiting multiple antiapoptotic factors. More importantly, similar effects were observed in other leukemia cell lines irrespective of their origin. The enhancement was observed regardless of PPAR expression and was not blocked even by peroxisome proliferator-activated receptor- (PPAR) siRNA. These results indicate that 15d-PGJ2 sensitizes TRAIL-resistant cells to TRAIL in a PPAR-independent manner and that the use of 15d-PGJ2 or its inducers, such as FCB, is a new strategy for cancer therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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