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Blood, 15 January 2006, Vol. 107, No. 2, pp. 679-688.
Prepublished online as a Blood First Edition Paper on September 29, 2005October 4, 2005; DOI 10.1182/blood-2005-05-1982.
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Submitted May 17, 2005
Accepted August 29, 2005
Dihydroflavonol BB-1, an extract of natural plant Blumea balsamifera, abrogates TRAIL resistance in leukemia cells
Hiroo Hasegawa, Yasuaki Yamada*, Kanki Komiyama, Masahiko Hayashi, Masami Ishibashi, Tatsushi Yoshida, Toshiyuki Sakai, Takashi Koyano, Toh-Seok Kam, Ken Murata, Kazuyuki Sugahara, Kazuto Tsuruda, Norihiko Akamatsu, Kunihiro Tsukasaki, Masato Masuda, Nobuyuki Takasu, and Shimeru Kamihira
Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Second Department of Internal Medicine, University of the Ryukyus, Okinawa, Japan
Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
The Kitasato Institute, Tokyo, Japan
Kitasato Institute for Life Sciences, Kitasato University, Tokyo, Japan
Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
Department of Molecular-Targeting, Cancer Prevention, Kyoto Prefectural University of Medicine,Graduate school of medical Science, Kyoto, Japan
Temko Corporation, Tokyo, Japan
Department of Chemistry, University of Malaya, Kulua Lumpur, Malaysia
Department of Hematology, Atomic Disease Institute, Nagasaki University School of Medicine, Nagasaki, Japan
Second Department of Internal Medicine, University of the Ryukyus, Okinawa, Japan
* Corresponding author; email: y-yamada{at}net.nagasaki-u.ac.jp.
TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in many transformed cells but not in normal cells, and hence has emerged as a novel anti-cancer agent. Previously, we showed that although most adult T-cell Leukemia/Lymphoma (ATLL) cells express the TRAIL death receptors DR4 (TRAIL-R1) and/or DR5 (TRAIL-R2), they are resistant to TRAIL. We thus tried to find natural products that can overcome TRAIL-resistance in this study. Among more than 150 materials screened, a dihydroflavonol that was extracted from Blumea balsamifera (BB-1) exhibited the most striking synergism with TRAIL. Treatment of the TRAIL-resistant ATLL cell line KOB with a combination of BB-1 and TRAIL resulted in apparent apoptotic cell death, which was not observed on treatment with either agent alone. Furthermore, pretreatment with BB-1 followed by TRAIL further augmented the synergism. BB-1 increased the level of TRAIL-R2 promoter activity as well as surface protein expression in a p53-independent manner. TRAIL-R2 siRNA inhibited the synergism indicating that the sensitization is due to the increase of TRAIL-R2 expression. More interestingly, similar effects were observed in other leukaemia cell lines via exactly the same mechanisms. These results suggest that combined treatment with BB-1 and TRAIL may be a new strategy for cancer-therapy.
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