2. Academic Validation
  3. Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia

Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia

  • Cancer Cell. 2017 Oct 9;32(4):490-505.e10. doi: 10.1016/j.ccell.2017.09.001.
Denis E Reyna 1,  Thomas P Garner 1,  Andrea Lopez 1,  Felix Kopp 2,  Gaurav S Choudhary 3,  Ashwin Sridharan 3,  Swathi-Rao Narayanagari 4,  Kelly Mitchell 4,  Baoxia Dong 3,  Boris A Bartholdy 4,  Loren D Walensky 5,  Amit Verma 3,  Ulrich Steidl 4,  Evripidis Gavathiotis 6
Affiliations

Affiliations

  • 1 Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 2 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 3 Department of Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, USA.
  • 4 Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 5 Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 6 Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: evripidis.gavathiotis@einstein.yu.edu.
PMID: 29017059 DOI: 10.1016/j.ccell.2017.09.001
Abstract

The Bcl-2 Family protein Bax is a central mediator of Apoptosis. Overexpression of anti-apoptotic Bcl-2 proteins contributes to tumor development and resistance to therapy by suppressing Bax and its activators. We report the discovery of BTSA1, a pharmacologically optimized Bax Activator that binds with high affinity and specificity to the N-terminal activation site and induces conformational changes to Bax leading to BAX-mediated Apoptosis. BTSA1-induced Bax activation effectively promotes Apoptosis in leukemia cell lines and patient samples while sparing healthy cells. Bax expression levels and cytosolic conformation regulate sensitivity to BTSA1. BTSA1 potently suppressed human acute myeloid leukemia (AML) xenografts and increased host survival without toxicity. This study provides proof-of-concept for direct Bax activation as a treatment strategy in AML.

Keywords

BAX; BAX activator; BCL-2 family; BH3; BTSA1; MOMP; apoptosis; cell death; leukemia; mitochondria.

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