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Prepublished online as a Blood First Edition Paper on July 31, 2003; DOI 10.1182/blood-2003-01-0108.
Submitted January 14, 2003
Accepted July 5, 2003
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 Mohammad, 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*
Departments of Medicine and Pathology, John D. Dingell VA Medical Center, Detroit, MI, USA; Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
Burnham Institute, La Jolla, CA, USA
Molecular Medicine Research Institute, Mountain View, CA, USA
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada
Laboratory of Molecular Pharmacology, College of Pharmacy, Oregon State University, Corvallis, OR, USA
Cancer Center, University of New Mexico, Albuquerque, NM, USA
* Corresponding author; email: Joseph.Fontana{at}Med.VA.gov.
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) which induces apoptosis in the tRA-resistant leukemia cell lines M07e, KG-1 and HL-60R, and tRA-resistant patient leukemic blasts. 3-Cl-AHPC totally inhibits leukemia colony formation at concentrations which inhibit committed human bone marrow stem cell proliferation i.e. granulocyte/ macrophage colony forming units (GM-CFU) by only 30%. Exposure to 3-Cl-AHPC results in caspase activation and the cleavage of poly-(ADP) ribose polymerase. While activation of the ERK and p38 pathways is not necessary for 3-Cl-AHPC-mediated apoptosis, maximal apoptosis requires JNK activation. 3-Cl-AHPC-mediated cleavage of the anti-apoptotic Bcl-XL protein to a pro-apoptotic 18 kD product is found in both the M07e cell line and patient leukemic blasts. 3-Cl-AHPC treatment of mice bearing the AML 1498 cell line results in a 3.3-log kill in the leukemic blasts. 3-Cl-AHPC, while not activating retinoic nuclear receptors is a potent inducer of apoptosis in AML cells and may represent a novel therapy in the treatment of this disease.
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