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Cell Cycle, Cell Death, and Senescence

A Retinoid/Butyric Acid Prodrug Overcomes Retinoic Acid Resistance in Leukemias by Induction of Apoptosis¹

¹ Lady Davis Institute/SMBD Jewish General Hospital, Center for Translational Research in Cancer, McGill University, Montreal, Quebec, Canada;
² Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Petach Tikva, Israel;
³ Chemistry Department, Bar Ilan University, Ramat Gan, Israel; and
⁴ Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY

Requests for reprints: Wilson H. Miller, Jr., Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, 3755 Cote Ste Catherine Road, Montreal, Quebec, H3T 1E2 Canada. Phone: (514) 340-8222 ext. 4365; Fax: (514) 340-7573. E-mail: wmiller{at}ldi.jgh.mcgill.ca

Some success in overcoming retinoic acid (RA)-resistance has been reported for acute promyelocytic leukemia in cell lines and the clinic by combining histone deacetylase inhibitors, like sodium butyrate (NaB), with RA. This epigenetic therapy counteracts the effects of nuclear corepressors, causing a DNA conformation that facilitates RA-induced gene transcription and cell differentiation. In an effort to improve delivery of each drug, we have synthesized retinoyloxymethyl butyrate (RN1), a mutual prodrug of both RA and butyric acid. RN1 targets both drugs to the same cells or cellular compartments to achieve differentiation at lower concentrations than using RA and NaB alone. In an RA-resistant cell line, which is not responsive to RA and NaB given together at the same concentration, RN1 inhibited growth substantially. This growth inhibition is caused by an increase in apoptosis and a minimal induction of differentiation, rather than the more complete granulocytic differentiation as seen in the RA-sensitive cell line. The different phenotypes induced by RN1 in RA-sensitive versus RA-resistant cells are reflected by altered patterns of gene expression. In addition to acute promyelocytic leukemia cells, RN1 induces apoptosis of other RA-resistant leukemic cell lines with blocked transcriptional pathways, but not normal human peripheral blood mononuclear cells. RN1, therefore, is a novel retinoid that may be more widely active in hematologic malignancies than RA alone.

Key Words: Leukemias • Retinoids • Apoptosis