WP744, a novel anthracycline with enhanced proapoptotic and antileukemic activity.
BACKGROUND
MDR1 or MRP1 drug resistance mechanisms seriously limit the efficacy of anthracyclines such as doxorubicin, in the treatment of acute myeloid leukemia (AML). Our studies indicated that reducing basicity, increasing steric hindrance at C-4', and/or lipophilicity may help circumvent P-glycoprotein (P-gp)-mediated anthracycline efflux and thus increase drug retention in MDR-positive cells. From a series of 4'-substituted analogs, 4'-O-benzylated doxorubicin (WP744) was selected for a comparison with the classic anthracycline doxorubicin for their cytotoxic and pro-apoptotic properties. WP744 retains cytotoxic activity against P-gp and MRP-positive cells.


RESULTS
In three AML cell lines (K562, KBM-3, and OCIM2) WP744 was markedly more potent (IC50 values of 0.18, <0.05, and <0.05 microg/ml, respectively) than doxorubicin (IC50 values of >0.5, 0.07, and 0.09 microg/ml, respectively). Likewise, WP744 inhibited the colony formation by AML-CFU cells from fresh bone marrow of three AML patients more strongly than doxorubicin. Cell growth inhibition by WP744 is accompanied by apoptosis induction as shown by TUNEL assay in OCIM2 cells. WP744-induced apoptosis appears to be mediated by caspase-3 as apoptotic changes were abrogated in the presence of the caspase 3 inhibitor Z-DEVD-FMK. Accordingly, caspase 3 activity was elevated in the lysates from drug-treated cells. WP744 induced also cleavage of apoptotic marker poly(ADP-ribose)polymerase (PARP). Finally, WP744 at 0.05 microM and greater was a potent inducer of apoptosis (by quantitative DNA fragmentation) in cultured human acute lymphoblastic leukemia (ALL) CEM cells, compared to 0.5 microM doxorubicin needed for a similar effect.


CONCLUSIONS
The novel anthracycline WP744 was found to be an antileukemic agent with proapoptotic activity superior to that of doxorubicin.
Faderl
S
S
The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Estrov
Z
Z
Kantarjian
H M
HM
Harris
D
D
Van
Q
Q
Fokt
I
I
Przewloka
T
T
Godlewski
C
C
Woynarowski
J M
JM
Priebe
W
W
D000328:Adult; D000368:Aged; D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D053938:DNA Fragmentation; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells / Q000187:drug effects / Q000473:pathology; D007948:Leukemia, Monocytic, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D006131:Growth Inhibitors; C451735:WP 744; D004317:Doxorubicin; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases