Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog

Blood. 2003 Nov 15;102(10):3743-52. doi: 10.1182/blood-2003-01-0108. Epub 2003 Jul 31.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adamantane / analogs & derivatives
  • Adamantane / pharmacology*
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis*
  • Caspases / metabolism
  • Cell Division / drug effects
  • Cinnamates / pharmacology*
  • Drug Resistance, Neoplasm*
  • Female
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Mice
  • Mice, Inbred Strains
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / drug effects
  • Poly(ADP-ribose) Polymerases / metabolism
  • Retinoids / pharmacology*
  • Signal Transduction
  • Tumor Cells, Cultured


  • 4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid
  • Antineoplastic Agents
  • CD 437
  • Cinnamates
  • Retinoids
  • Poly(ADP-ribose) Polymerases
  • Caspases
  • Adamantane