N-(4-Hydroxylphenyl)retinamide (fenretinide, 4-HPR), a retinoid compound with antileukemic and proapoptotic activity in acute lymphoblastic leukemia (ALL).
BACKGROUND
Retinoids have been shown to regulate vital cellular processes including cell proliferation, differentiation and apoptosis. N-(4-Hydroxyphenyl)-all-trans-retinamide (fenretinide, 4-HPR) is a synthetic ATRA derivative with chemopreventive and cytotoxic activity against various cancer cell lines including myeloid leukemia. Although several modes of action have been postulated, its mechanism of action in hematologic malignancies remains unclear. Furthermore, only limited information exists as to its activity in lymphoid malignancies.


RESULTS
To test whether 4-HPR has activity in acute lymphoblastic leukemia (ALL), we first analyzed its antiproliferative effect in five ALL (Z-33, Z-138, Z-119, Z-181, and Jurkat) cell lines. We found that 4-HPR inhibited the proliferation of all cell lines in a dose-dependent manner at concentrations ranging from 1 to 10 microM. We further demonstrated by cell cycle analysis that 5 microM of 4-HPR blocked Z-119 cells in S phase thus preventing their progression through the cycle. Next we tested whether 4-HPR activated the caspase pathway and induced apoptotic cell death. We found that 4-HPR induced apoptosis in Z-119 cells through the activation of caspase-3 and subsequent cleavage of its substrate poly(ADP-ribose) polymerase (PARP). We then asked whether 4-HPR could affect fresh ALL progenitor cells. Therefore, we obtained bone marrow and peripheral blood cells from five patients with newly diagnosed ALL and tested the effect of 4-HPR using the ALL blast colony culture assay. To supplement our results, we also performed the ALL blast assay on one ALL cell line (ALL-1). We found that 4-HPR significantly inhibited ALL colony-forming cell proliferation in a dose-dependent manner.


CONCLUSIONS
Our data show that 4-HPR is a potent inhibitor of ALL cell proliferation and that it induces in vitro apoptotic cell death in ALL blasts. Further studies are warranted to establish the in vivo effect of 4-HPR particularly in patients with ALL.
Faderl
Stefan
S
Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, P.O. Box 428, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Lotan
Reuben
R
Kantarjian
Hagop M
HM
Harris
David
D
Van
Quin
Q
Estrov
Zeev
Z
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001773:Blood Cells / Q000473:pathology; D001854:Bone Marrow Cells / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D007399:Interphase / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology*; D012176:Retinoids / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D012176:Retinoids; D017313:Fenretinide; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases