Context-selective death of acute myeloid leukemia cells triggered by the novel hybrid retinoid-HDAC inhibitor MC2392

Floriana De Bellis, Vincenzo Carafa, Mariarosaria Conte, Dante Rotili, Francesca Petraglia, Filomena Matarese, Kees Jan Françoijs, Julien Ablain, Sergio Valente, Rémy Castellano, Armelle Goubard, Yves Collette, Amit Mandoli, Joost H.A. Martens, Hugues De Thé, Angela Nebbioso, Antonello Mai, Hendrik G. Stunnenberg, Lucia Altucci

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

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-RARa oncofusion protein ismediated 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-RARa- 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-RARa, MC2392 induces changes in H3 acetylation at a small subset of PML-RARa-binding sites. RNA-seq reveals that MC2392 alters expression of a number of stress-responsive and apoptotic genes. Concordantly, MC2392 induced rapid andmassive, 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-RARa conveys efficient MC2392-induced cell death. Our data suggest a model in which MC2392 binds to the RARa 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.

Original languageEnglish
Pages (from-to)2328-2339
Number of pages12
JournalCancer Research
Volume74
Issue number8
DOIs
Publication statusPublished - 15 Apr 2014
Externally publishedYes

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