Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog.
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.
Zhang
Yuxiang
Y
John D Dingell VA Medical Center, and Department of Medicine, Wayne State University, Detroit, MI 48201, USA.
Dawson
Marcia I
MI
Ning
Yangmin
Y
Polin
Lisa
L
Parchment
Ralph E
RE
Corbett
Thomas
T
Mohamed
Anwar N
AN
Feng
Kai-Chia
KC
Farhana
Lulu
L
Rishi
Arun K
AK
Hogge
Donna
D
Leid
Mark
M
Peterson
Valerie J
VJ
Zhang
Xiao-kun
XK
Mohammad
Ramzi
R
Lu
Jing-Song
JS
Willman
Cheryl
C
VanBuren
Eric
E
Biggar
Sandra
S
Edelstein
Mark
M
Eilender
David
D
Fontana
Joseph A
JA
D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
C480030:4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid; D000970:Antineoplastic Agents; C099555:CD 437; D002934:Cinnamates; D012176:Retinoids; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D000218:Adamantane