Abstract
HDAC inhibitors (HDACi) are widely used in the clinic to sensitize tumorigenic cells for treatment with other anticancer compounds. The major drawback of HDACi is the broad inhibition of the plethora of HDAC-containing complexes. In acute promyelocytic leukemia (APL), repression by the PML-RARα oncofusion protein is mediated by an HDAC-containing complex that can be dissociated by pharmacologic doses of all trans retinoic acid (ATRA) inducing differentiation and cell death at the expense of side effects and recurrence. We hypothesized that the context-specific close physical proximity of a retinoid and HDACi-binding protein in the repressive PML-RARα-HDAC complex may permit selective targeting by a hybrid molecule of ATRA with a 2-aminoanilide tail of the HDAC inhibitor MS-275, yielding MC2392. We show that MC2392 elicits weak ATRA and essentially no HDACi activity in vitro or in vivo. Genome-wide epigenetic analyses revealed that in NB4 cells expressing PML-RARα, MC2392 induces changes in H3 acetylation at a small subset of PML-RARα-binding sites. RNA-seq reveals that MC2392 alters expression of a number of stress-responsive and apoptotic genes. Concordantly, MC2392 induced rapid and massive, caspase-8-dependent cell death accompanied by RIP1 induction and ROS production. Solid and leukemic tumors are not affected by MC2392, but expression of PML-RARα conveys efficient MC2392-induced cell death. Our data suggest a model in which MC2392 binds to the RARα moiety and selectively inhibits the HDACs resident in the repressive complex responsible for the transcriptional impairment in APLs. Our findings provide proof-of-principle of the concept of a context-dependent targeted therapy.
Highlights
Acute promyelocytic leukemia is characterized by the presence of blasts blocked at the promyelocytic stage of myeloid differentiation and by the fusion protein of RARa with the Authors' Affiliations: 1Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Universita degli Studi di Napoli; 2Istituto di Genetica e Biofisica, IGB, Adriano Buzzati Traverso, Naples; 3Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, Rome, Italy; 4NCMLS, Radboud University, Nijmegen, the Netherlands; 5Inserm, CRCM, U1068, TrGET & ISCB, University of Marseille; and 6Laboratoire U944 and UMR 7212, University Paris-Diderot, Paris, FranceNote: Supplementary data for this article are available at Cancer Research Online.Ó2014 American Association for Cancer Research.promyelocytic leukemia gene (PML) in more than 95% of the cases [1, 2]
We set out to exploit the possibility to combine the active parts of the HDAC inhibitors (HDACi) MS-275 and the retinoid, all trans retinoic acid (ATRA), yielding MC2392 (Fig. 1A)
Epigenetic modifications can be reversed by epi-drugs that are promising for antitumor therapy
Summary
Acute promyelocytic leukemia is characterized by the presence of blasts blocked at the promyelocytic stage of myeloid differentiation and by the fusion protein of RARa with the Authors' Affiliations: 1Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Universita degli Studi di Napoli; 2Istituto di Genetica e Biofisica, IGB, Adriano Buzzati Traverso, Naples; 3Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, Rome, Italy; 4NCMLS, Radboud University, Nijmegen, the Netherlands; 5Inserm, CRCM, U1068, TrGET & ISCB, University of Marseille; and 6Laboratoire U944 and UMR 7212, University Paris-Diderot, Paris, FranceNote: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).Ó2014 American Association for Cancer Research.promyelocytic leukemia gene (PML) in more than 95% of the cases [1, 2]. In the treatment of APL, the efficacy of pharmacologic doses of ATRA is due to its ability to release the HDAC-containing repressive complexes bound to PML-RARa [6] and to recruit the multi-subunit HAT complex on RARE. Besides having this desired therapeutic effect on APL blasts, ATRA binds to and activates the nuclear receptors (RARa, b, or g) that bind to specific DNA responsive elements HDACi cause enzymatic inhibition and/or the release of HDACs from repressive complexes permitting HAT recruitment, histone acetylation, chromatin decondensation and, transcription activation of tumor-suppressor genes (TSG) or other genes crucial for the normal functioning of the cells [7]. The major drawback of HDACi in treatment is the broad inhibition of the plethora of HDAC-containing complexes
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