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Context-selective death of acute myeloid leukemia cells triggered by the novel hybrid retinoid-HDAC inhibitor MC2392.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Bellis, Floriana De Carafa, Vincenzo Conte, Mariarosaria Rotili, Dante Petraglia, Francesca Matarese, Filomena Françoijs, Kees-Jan Ablain, Julien Valente, Sergio Castellano, Renata Goubard, Armelle Angélique Collette, Yves Mandoli, Amit Martens, Joost H. A. Thé, Hugues De Nebbioso, Angela Cappellacci, Loredana Stunnenberg, Hendrik G. Altucci, Lucia |
| Copyright Year | 2014 |
| 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. |
| Starting Page | 1 |
| Ending Page | 11 |
| Page Count | 11 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/early/2014/02/22/0008-5472.CAN-13-2568.full.pdf |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/74/8/2328.full.pdf |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/early/2014/03/31/0008-5472.CAN-13-2568.full.pdf |
| PubMed reference number | 24566867v1 |
| Alternate Webpage(s) | https://doi.org/10.1158/0008-5472.CAN-13-2568 |
| DOI | 10.1158/0008-5472.can-13-2568 |
| Journal | Cancer research |
| Volume Number | 74 |
| Issue Number | 8 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Acute Promyelocytic Leukemia Angiotensin-Converting Enzyme Inhibitors Binding Sites Cell Death Cessation of life Histone deacetylase inhibitor Leukemia, Myelocytic, Acute Leukoencephalopathy, Progressive Multifocal MS 27-275 Myeloid Leukemia Pharmacology Pituitary Neoplasms Probable Transcription Factor PML RNA Repression, Psychology Retinoids Sequence Number Subgroup Transcription, Genetic Tretinoin cellular targeting study of epigenetics |
| Content Type | Text |
| Resource Type | Article |
