A novel retinoic/butyric hyaluronan ester for the treatment of acute promyelocytic leukemia: preliminary preclinical results.
All-trans retinoic acid (ATRA) represents the therapy of choice for patients with acute promyelocytic leukemia (APL). However, patients often relapse due to ATRA-resistance. The molecular basis of APL alterations indicates that addition of a histone deacetylase inhibitor to ATRA may restore the sensitivity to retinoids. We explored the in vitro and in vivo effects of a novel retinoic/butyric hyaluronan ester (HBR) on a retinoic acid (RA)-sensitive human myeloid cell line, NB4, and on its RA-resistant subclone, NB4.007/6. In vitro, HBR induced growth arrest and terminal differentiation in RA-sensitive NB4 cells (as confirmed by an increased expression of CD11 family members and nitroblue tetrazolium assay), whereas it inhibited the growth of RA-resistant cells by apoptosis, paralleled by an increase in the levels of caspase 3 and 7. In vivo, HBR treatment of NB4-inoculated severe combined immunodeficient mice resulted in a statistically significant increase in survival time (P<0.0001), comparable to that induced by a maximum tolerated dose of RA alone. Also on P388-inoculated mice, HBR was active in contrast to RA that was completely ineffective. Present findings suggest that, owing to the simultaneous presence of RA and an histone deacetylases inhibitor, HBR might be useful in controlling the proliferation of RA-resistant cells and the differentiation of RA-sensitive cells.
Coradini
D
D
Unit of Tumor Biology and Experimental Therapy, Experimental Department, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy. danila.coradini@istitutotumori.mi.it
Pellizzaro
C
C
Scarlata
I
I
Zorzet
S
S
Garrovo
C
C
Abolafio
G
G
Speranza
A
A
Fedeli
M
M
Cantoni
S
S
Sava
G
G
Daidone
M G
MG
Perbellini
A
A
D017209:Apoptosis / Q000187:drug effects; D020148:Butyric Acid / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000187:drug effects / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004952:Esters / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D009363:Neoplasm Proteins / Q000187:drug effects; D015514:Oncogene Proteins, Fusion / Q000187:drug effects; D011485:Protein Binding; D014212:Tretinoin / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D022763:CCAAT-Enhancer-Binding Protein-alpha; D022782:CCAAT-Enhancer-Binding Protein-beta; D004952:Esters; D006657:Histones; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D020148:Butyric Acid; D014212:Tretinoin; D006820:Hyaluronic Acid