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Blood, 15 November 2003, Vol. 102, No. 10, pp. 3743-3752. Prepublished online as a Blood First Edition Paper on July 31, 2003; DOI 10.1182/blood-2003-01-0108. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-01-0108v1 102/10/3743    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zhang, Y. Articles by Fontana, J. A. Search for Related Content PubMed PubMed Citation Articles by Zhang, Y. Articles by Fontana, J. A. Related Collections Hematopoiesis and Stem Cells Neoplasia Apoptosis Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog Yuxiang Zhang, Marcia I. Dawson, Yangmin Ning, Lisa Polin, Ralph E. Parchment, Thomas Corbett, Anwar N. Mohamed, Kai-Chia Feng, Lulu Farhana, Arun K. Rishi, Donna Hogge, Mark Leid, Valerie J. Peterson, Xiao-kun Zhang, Ramzi Mohammad, Jing-Song Lu, Cheryl Willman, Eric VanBuren, Sandra Biggar, Mark Edelstein, David Eilender, and Joseph A. Fontana From the John D. Dingell VA Medical Center; the Departments of Medicine and Pathology, and the Karmanos Cancer Institute, Wayne State University, Detroit, MI; Burnham Institute, La Jolla, CA; Molecular Medicine Research Institute, Mountain View, CA; Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada; the Department of Medicine and Medical Genetics, University of British Columbia, Vancouver, BC, Canada; Laboratory of Molecular Pharmacology, College of Pharmacy, Oregon State University, Corvallis; and University of New Mexico Cancer Center, University of New Mexico, Albuquerque. Acute myelogenous leukemia (AML) is a heterogeneous disease consisting of a variety of different leukemic subtypes. While acute promyelocytic leukemia displays marked sensitivity to the differentiating effects of trans-retinoic acid (tRA), other subtypes of AML display resistance. We now describe a novel compound (E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC/MM002) that induces apoptosis in the tRA-resistant leukemia cell lines M07e, KG-1, and HL-60R, and in tRA-resistant patient leukemic blasts. The 3-Cl-AHPC totally inhibits leukemia colony formation at concentrations that inhibit committed human bone marrow stem cell proliferation, that is, granulocyte/macrophage colony-forming units (CFU-GMs) by only 30%. Exposure to 3-Cl-AHPC results in caspase activation and the cleavage of poly(adenosine diphosphate) (poly(ADP)) ribose polymerase. While activation of the extracellular signal-regulated kinase (ERK) and p38 pathways is not necessary for 3-Cl-AHPC-mediated apoptosis, maximal apoptosis requires c-Jun N-terminal kinase (JNK) activation. The 3-Cl-AHPC-mediated cleavage of the antiapoptotic B-cell leukemia XL (Bcl-XL) protein to a proapoptotic 18-kDa product is found in both the M07e cell line and patient leukemic blasts. The 3-Cl-AHPC treatment of mice bearing the AML 1498 cell line results in a 3.3-log kill in the leukemic blasts. While 3-Cl-AHPC does not activate retinoic nuclear receptors, it is a potent inducer of apoptosis in AML cells and may represent a novel therapy in the treatment of this disease. (Blood. 2003; 102:3743-3752) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. Farhana, M. I. Dawson, M. Leid, L. Wang, D. D. Moore, G. Liu, Z. Xia, and J. A. Fontana Adamantyl-Substituted Retinoid-Related Molecules Bind Small Heterodimer Partner and Modulate the Sin3A Repressor Cancer Res., January 1, 2007; 67(1): 318 - 325. [Abstract] [Full Text] [PDF] L. Farhana, M. I. Dawson, and J. A. Fontana Apoptosis Induction by a Novel Retinoid-Related Molecule Requires Nuclear Factor-{kappa}B Activation Cancer Res., June 1, 2005; 65(11): 4909 - 4917. [Abstract] [Full Text] [PDF]

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