Adamantyl-substituted retinoid-related molecules induce apoptosis in human acute myelogenous leukemia cells.
The adamantyl-substituted retinoid-related (ARR) compounds 3-Cl-AHPC and AHP3 induce apoptosis in vitro and in vivo in a newly established human acute myelogenous leukemia (AML) cell line, FFMA-AML, and in the established TF(v-SRC) AML cell line. FFMA-AML and TF(v-SRC) cells displayed resistance to apoptosis mediated by the standard retinoids (including trans-retinoic acid, 9-cis-retinoic acid, and the synthetic retinoid TTNPB) but showed sensitivity to apoptosis mediated by 3-Cl-AHPC- and AHP3 in vitro and in vivo as documented by poly(ADP-ribose) polymerase (PARP) cleavage and apoptosis terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling assay. 3-Cl-AHPC or AHP3 exposure in vitro resulted in decreased expression of the antiapoptotic proteins (cellular inhibitor of apoptosis 1, X-linked inhibitor of apoptosis protein) and phospho-Bad and activated the NF-κB canonical pathway. A significant prolongation of survival was observed both in nonobese diabetic severe combined immunodeficient mice carrying FFMA-AML cells and treated with either 3-Cl-AHPC or AHP3 and in severe combined immunodeficient mice carrying TF(v-SRC) cells and treated with AHP3. We have previously shown that ARRs bind to the orphan nuclear receptor small heterodimer partner (SHP) and that the expression of SHP is required for ARR-mediated apoptosis. Induced loss of SHP in these AML cells blocked 3-Cl-AHPC- and AHP3-mediated induction of apoptosis. These results support the further development of 3-Cl-AHPC and AHP3 as potential therapeutic agents in the treatment of AML patients.
John D. Dingell VA Medical Center, Wayne State University, Karmanos Cancer Institute, Oncology 11M-HO, Room C3540, 4646 John R. Street, Detroit, MI 48201, USA.
Lulu
L
Farhana
Marcia I
MI
Dawson
Zebin
Z
Xia
Amro
A
Aboukameel
Liping
L
Xu
Gang
G
Liu
Jayanta K
JK
Das
James
J
Hatfield
Edi
E
Levi
Ramzi
R
Mohammad
Joseph A
JA
Fontana
D000179:Acrylates / Q000737:chemistry / Q000494:pharmacology; D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D051379:Mice; D008813:Mice, Inbred ICR; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D012176:Retinoids / Q000737:chemistry* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C556168:3-(2-(3-(1-adamantyl)-4-hydroxyphenyl)-5-pyrimidinyl)-2-propenoic acid; C480030:4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid; D000179:Acrylates; D000970:Antineoplastic Agents; D002934:Cinnamates; D012176:Retinoids; D000218:Adamantane