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Prepublished online as a Blood First Edition Paper on July 12, 2002; DOI 10.1182/blood-2002-02-0567.
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Blood, 1 November 2002, Vol. 100, No. 9, pp. 3319-3324
NEOPLASIA
The histone deacetylase inhibitor AN-9 has selective toxicity to
acute leukemia and drug-resistant primary leukemia and cancer cell
lines
Ayse Batova,
Li-en Shao,
Mitchell B. Diccianni,
Alice L.Yu,
Tetsuya Tanaka,
Ada Rephaeli,
Abraham Nudelman, and
John Yu
From the Division of Pediatric Hematology/Oncology,
Department of Pediatrics, University of California San Diego;
Department of Immunology, The Scripps Research Institute, La Jolla, CA;
Felsenstein Medical Research Center, Sackler School of Medicine, Tel
Aviv University, Beilinson Campus, Petach Tikva, Israel; and the
Chemistry Department, Bar Ilan University, Ramat Gan, Israel.
The novel prodrug of butyric acid, pivaloyloxymethyl butyrate
(AN-9), a histone deacetylase inhibitor, shows great promise as an
effective and relatively nontoxic anticancer agent for solid malignancies. However, little is known about its effects on
hematopoietic malignancies. In this study, we show that 21 primary
samples of acute leukemia were sensitive to the antiproliferative
effects of AN-9, with a 50% inhibitory concentration
(IC50) of 45.8 ± 4.1 µM. In colony-forming assays,
primary T-cell acute lymphoblastic leukemia (T-ALL) cells were 3-fold
more sensitive to AN-9 than the normal hematopoietic progenitors,
erythroid burst-forming units and granulocyte/monocyte
colony-forming units. AN-9 induced apoptosis in the T-ALL cell
line CEM. A common problem with cancer is chemoresistance, which is
often typical of relapsed cancers. Remarkably, a T-ALL sample at
diagnosis and an acute myeloid leukemia sample at relapse that were
resistant to doxorubicin in vitro were sensitive to AN-9, with
an IC50 of 50 µM for both samples. More strikingly,
samples from 2 infants with t(4;11) ALL obtained at diagnosis and
relapse each were the most sensitive to AN-9, with IC50
values of 25 µM and 17 µM, respectively. Furthermore, a
doxorubicin-resistant clone of HL60, HL60/ADR, obtained by the transfection of the MDR-1 gene, was equally
sensitive to AN-9 cytotoxicity as the parental cells. AN-9 induced the
expression of p21 in an infant leukemia sample with 11q23
rearrangement, but not in T- or B-precursor ALL. Collectively, our
results suggest that AN-9 is a selective agent for hematopoietic
malignancies that can circumvent the mechanisms of chemoresistance
limiting most conventional chemotherapy.
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