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 EdelsteinDavid Eilender, Joseph A. Fontana

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)3743-3752
Number of pages10
Issue number10
StatePublished - Nov 15 2003

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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