title: Context-selective death of acute myeloid leukemia cells triggered by the novel hybrid retinoid-HDAC inhibitor MC2392.
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.
authors.affiliation: Authors' Affiliations: Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università degli Studi di Napoli; Istituto di Genetica e Biofisica, IGB, Adriano Buzzati Traverso, Naples; Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, Rome, Italy; NCMLS, Radboud University, Nijmegen, the Netherlands; Inserm, CRCM, U1068, TrGET & ISCB, University of Marseille; and Laboratoire U944 and UMR 7212, University Paris-Diderot, Paris, France.
authors.forename: Floriana
authors.initials: F
authors.lastname: De Bellis
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Carafa
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Conte
authors.forename: Dante
authors.initials: D
authors.lastname: Rotili
authors.forename: Francesca
authors.initials: F
authors.lastname: Petraglia
authors.forename: Filomena
authors.initials: F
authors.lastname: Matarese
authors.forename: Kees-Jan
authors.initials: KJ
authors.lastname: Françoijs
authors.forename: Julien
authors.initials: J
authors.lastname: Ablain
authors.forename: Sergio
authors.initials: S
authors.lastname: Valente
authors.forename: Rèmy
authors.initials: R
authors.lastname: Castellano
authors.forename: Armelle
authors.initials: A
authors.lastname: Goubard
authors.forename: Yves
authors.initials: Y
authors.lastname: Collette
authors.forename: Amit
authors.initials: A
authors.lastname: Mandoli
authors.forename: Joost H A
authors.initials: JH
authors.lastname: Martens
authors.forename: Hugues
authors.initials: H
authors.lastname: de Thé
authors.forename: Angela
authors.initials: A
authors.lastname: Nebbioso
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
mesh_terms: D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death; D002454:Cell Differentiation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D020298:U937 Cells
chemical_list: D056572:Histone Deacetylase Inhibitors; D015514:Oncogene Proteins, Fusion; D017382:Reactive Oxygen Species; D012176:Retinoids; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; C505530:CASP8 protein, human; D053181:Caspase 8