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Blood, 1 September 2005, Vol. 106, No. 5, pp. 1794-1800. Prepublished online as a Blood First Edition Paper on May 3, 2005; DOI 10.1182/blood-2005-01-0346. This Article Full Text (PDF) All Versions of this Article: 2005-01-0346v1 106/5/1794    most recent Alert me when this article is cited Alert me if a correction is posted 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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ishitsuka, K. Articles by Anderson, K. C Search for Related Content PubMed PubMed Citation Articles by Ishitsuka, K. Articles by Anderson, K. C Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 27, 2005 Accepted April 25, 2005 Honokiol overcomes conventional drug resistance in human multiple myeloma by induction of caspase-dependent and independent apoptosis Kenji Ishitsuka, Teru Hideshima, Makoto Hamasaki, Noopur Raje, Shaji Kumar, Hiromasa Hideshima, Norihiko Shiraishi, Hiroshi Yasui, Aldo M Roccaro, Paul Richardson, Klaus Podar, Steven Le Gouill, Dharminder Chauhan, Kazuo Tamura, Jack Arbiser, and Kenneth C Anderson* Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA 1st Department of Internal Medicine, Fukuoka University, Fukuoka, Japan Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA * Corresponding author; email: kenneth_anderson{at}dfci.harvard.edu. Honokiol (HNK) is an active component purified from Magnolia, a plant used in traditional Chinese and Japanese medicine. Here we show that HNK significantly induces cytotoxicity in human multiple myeloma (MM) cell lines and tumor cells from patients with relapsed refractory MM. Neither co-culture with bone marrow stromal cells nor cytokines (interleukin-6 and insulin-like growth factor-1) protect against HNK-induced cytotoxicity. Although, activation of caspases 3, 7, 8 and 9 is triggered by HNK, the pan-caspase inhibitor z-VAD-fmk does not abrogate HNK-induced apoptosis. Importantly, release of an executioner of caspase-independent apoptosis, apoptosis-inducing factor (AIF) from mitochondria is induced by HNK treatment. HNK induces apoptosis in SU-DHL4 cell line, which has low levels of caspase-3 and -8 associated with resistance to both conventional and novel drugs. These results suggest that HNK induces apoptosis via both caspase-dependent and -independent pathways. Furthermore, HNK enhances MM cell cytotoxicity and apoptosis induced by bortezomib. In addition to its direct cytotoxicity to MM cells, HNK also represses tube formation by endothelial cells, suggesting that HNK inhibits neovascurization in the bone marrow microenvironment. Taken together, our results provide the preclinical rationale for clinical protocols of HNK to improve patient outcome in MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Old and new drugs join forces against hematologic malignancies Fabio Malavasi Blood 2005 106: 1513-1514. [Full Text] [PDF] This article has been cited by other articles: S. M. Raja, S. Chen, P. Yue, T. M. Acker, B. Lefkove, J. L. Arbiser, F. R. Khuri, and S.-Y. Sun The natural product honokiol preferentially inhibits cellular FLICE-inhibitory protein and augments death receptor-induced apoptosis Mol. Cancer Ther., July 1, 2008; 7(7): 2212 - 2223. [Abstract] [Full Text] [PDF] E.-R. Hahm, J. A. Arlotti, S. W. Marynowski, and S. V. Singh Honokiol, a Constituent of Oriental Medicinal Herb Magnolia officinalis, Inhibits Growth of PC-3 Xenografts In vivo in Association with Apoptosis Induction Clin. Cancer Res., February 15, 2008; 14(4): 1248 - 1257. [Abstract] [Full Text] [PDF] E.-R. Hahm and S. V. Singh Honokiol causes G0-G1 phase cell cycle arrest in human prostate cancer cells in association with suppression of retinoblastoma protein level/phosphorylation and inhibition of E2F1 transcriptional activity Mol. Cancer Ther., October 1, 2007; 6(10): 2686 - 2695. [Abstract] [Full Text] [PDF] L. Li, W. Han, Y. Gu, S. Qiu, Q. Lu, J. Jin, J. Luo, and X. Hu Honokiol Induces a Necrotic Cell Death through the Mitochondrial Permeability Transition Pore Cancer Res., May 15, 2007; 67(10): 4894 - 4903. [Abstract] [Full Text] [PDF] K. S. Ahn, G. Sethi, S. Shishodia, B. Sung, J. L. Arbiser, and B. B. Aggarwal Honokiol Potentiates Apoptosis, Suppresses Osteoclastogenesis, and Inhibits Invasion through Modulation of Nuclear Factor-{kappa}B Activation Pathway Mol. Cancer Res., September 1, 2006; 4(9): 621 - 633. [Abstract] [Full Text] [PDF]

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