Synergistic antileukemic therapies in NOTCH1-induced T-ALL Academic Article uri icon

Overview

MeSH Major

  • Antineoplastic Combined Chemotherapy Protocols
  • Arsenicals
  • Leukemia, Promyelocytic, Acute
  • Oxides
  • Tretinoin

abstract

  • The Notch1 gene is a major oncogenic driver and therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL). However, inhibition of NOTCH signaling with γ-secretase inhibitors (GSIs) has shown limited antileukemic activity in clinical trials. Here we performed an expression-based virtual screening to identify highly active antileukemic drugs that synergize with NOTCH1 inhibition in T-ALL. Among these, withaferin A demonstrated the strongest cytotoxic and GSI-synergistic antileukemic effects in vitro and in vivo. Mechanistically, network perturbation analyses showed eIF2A-phosphorylation-mediated inhibition of protein translation as a critical mediator of the antileukemic effects of withaferin A and its interaction with NOTCH1 inhibition. Overall, these results support a role for anti-NOTCH1 therapies and protein translation inhibitor combinations in the treatment of T-ALL.

publication date

  • February 21, 2017

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5338362

Digital Object Identifier (DOI)

  • 10.1073/pnas.1611831114

PubMed ID

  • 28174276

Additional Document Info

start page

  • 2006

end page

  • 2011

volume

  • 114

number

  • 8