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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.
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Submitted January 18, 2007
Accepted May 31, 2007
A novel natural compound, a Cycloanthranilylproline-derivative (Fuligocandin B), sensitizes leukemia cells to TRAIL-induced apoptosis through 15d-PGJ2 production
Hiroo Hasegawa, Yasuaki Yamada*, Kanki Komiyama, Masahiko Hayashi, Masami Ishibashi, Toshiaki Sunazuka, Takeshi Izuhara, Kazuyuki Sugahara, Kazuto Tsuruda, Masato Masuda, Nobuyuki Takasu, Kunihiro Tsukasaki, Masao Tomonaga, and Shimeru Kamihira
Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
Kitasato Institute, Kitasato University, Tokyo, Japan
Kitasato Institute for Life Sciences, Kitasato University, Tokyo, Japan
Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan
Second Department of Internal Medicine, University of the Ryukyus, Okinawa, Japan
Department of Hematology, Atomic Disease Institute, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan
* Corresponding author; email: y-yamada{at}nagasaki-u.ac.jp.
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 non-toxic-drugs can be used together with TRAIL. We thus screened a number of natural compounds that can overcome resistance to TRAIL and found that Cycloanthranilylproline-derivative (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 15d-PGJ2, an endogenous PPAR ligand, through activation of COX-2. This unique mechanism highlighted that 15d-PGJ2 directly enhanced sensitivity to TRAIL by inhibiting multiple anti-apoptotic 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 by even 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.
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