MMD Masterclass

PML-RARα context-selective cell death triggered by the novel hybrid retinoid-HDAC-inhibitor MC2392 in AML

Date:
1 April 2014 00:00 hrs.
Location:
Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289
Title:
PML-RARα context-selective cell death triggered by the novel hybrid retinoid-HDAC-inhibitor MC2392 in AML
Speaker(s):

Dr. Lucia Altucci, Dip. Biochimica, Biofisica e Patologia generale, University of Napoli, Italy

Host(s):

Dr. Joost Martens,  Department of Molecular Biology, RIMLS

01-04-2014 00:00:00Europe/AmsterdamPML-RARα context-selective cell death triggered by the novel hybrid retinoid-HDAC-inhibitor MC2392 in AML  Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289Rimlsrimls@radboudumc.nl

Remarks / more information:

Altucci , LuciaHDAC inhibitors (HDACi) are widely used in the clinic to sensitize tumorigenic cells for treatment with other anticancer compounds. The major drawback 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 pharmacological 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.  Our findings provide proof-of-principle of the concept of a context-dependent targeted therapy.

Key Publications:

  • Context-selective death of acute myeloid leukemia cells triggered by the novel hybrid retinoid-HDAC inhibitor MC2392. Cancer Res. Feb. 2014.
  • Death receptor pathway activation and increase of ROS production by the triple epigenetic inhibitor UVI5008. Mol Cancer Ther. Dec 2011. 
  • Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nat Med. Jan 2005.

 

 



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