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Prepublished online as a Blood First Edition Paper on July 12, 2002; DOI 10.1182/blood-2002-02-0567.
Submitted February 25, 2002
Accepted April 30, 2002
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
Pediatrics, UCSD Medical Center, San Diego, CA, USA
Immunology, The Scripps Research Institute, La Jolla, CA, USA
Felsenstein Medical Research Center, Petach Tikva, Israel
Chemistry, Bar Ilan University, Ramat Gan, Israel
* Corresponding author; email: aliceyu{at}ucsd.edu.
The novel pro-drug of butyric acid, pivaloyloxymethyl butyrate (AN-9), a histone deacetylase inhibitor, shows great promise as an effective and relatively non-toxic anti-cancer agent for solid malignancies. However, little is known about its effects on hematological malignancies. In this study, we show that 21 primary samples of acute leukemia are sensitive to the anti-proliferative effects of AN-9 with an IC50 of 45.8 ± 4.1 µM. In colony forming assays, primary T-ALL cells were 3-fold more sensitive than the normal hematopoietic progenitors, BFU-E and CFU-GM, to AN-9. AN-9 induced apoptosis in the T-ALL cell line CEM. A common problem with cancer is chemo-resistance which is often typical of relapsed cancers. Remarkably, a diagnosis T-ALL and a relapse AML sample that were resistant to adriamycin in vitro, were sensitive to AN-9, with 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 of 25 µM and 17 µM, respectively. Furthermore, an adriamycin-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 indued expression of p21 in infant leukemia with 11 q23 rearrangement, but not in T- or B-precursor ALL. Collectively, our results suggest that AN-9 is a selective agent for hematological malignancies which can circumvent mechanisms of chemo-resistance limiting most conventional chemotherapy.
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