A retinoid/butyric acid prodrug overcomes retinoic acid resistance in leukemias by induction of apoptosis.
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.
Lady Davis Institute/SMBD Jewish General Hospital, Center for Translational Research in Cancer, McGill University, Montreal, Quebec, Canada.
Koren K
KK
Mann
Ada
A
Rephaeli
April L
AL
Colosimo
Zuanel
Z
Diaz
Abraham
A
Nudelman
Inesa
I
Levovich
Yongkui
Y
Jing
Samuel
S
Waxman
Wilson H
WH
Miller
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002087:Butyrates / Q000138:chemical synthesis / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004347:Drug Interactions; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism; D011355:Prodrugs; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002087:Butyrates; D011355:Prodrugs; C412732:retinoyloxymethyl butyrate; D014212:Tretinoin