Artesunate overcomes drug resistance in multiple myeloma by inducing mitochondrial stress and non-caspase apoptosis
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Xenofon Papanikolaou1, Sarah Johnson1, Tarun Garg1, Erming Tian1, Ruslana Tytarenko1, Qing Zhang1, Caleb Stein1, Bart Barlogie1, Joshua Epstein1 and Christoph Heuck1
1 Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR
Christoph Heuck, email:
Keywords: artesunate, apoptosis, caspases, myeloma, ROS
Received: February 18, 2014 Accepted: March 22, 2014 Published: March 24, 2014
Although novel drugs have contributed immensely to improving outcomes of patients with multiple myeloma (MM), many patients develop drug resistance and ultimately succumb to MM. Here, we show that artesunate, an anti-malarial drug, reliably induces cell death in vitro in naïve as well as drug-resistant MM cells at concentrations shown to be safe in humans. Artesunate induced apoptosis predominantly through the non-caspase mediated pathway by primarily targeting mitochondria and causing outer mitochondrial membrane permeabilization that led to cytosolic and subsequent nuclear translocation of mitochondrial proteins apoptosis inducing factor (AIF) and endonuclease G (EndoG). Nuclear translocation of AIF and EndoG was accompanied by low levels of reactive oxygen species (ROS) and increased mitochondrial production of superoxide. These effects were present before apoptosis was evident and were related to intracellular levels of bivalent iron (Fe+2). Artesunate’s unique mechanism probably was at least partially responsible for, its ability to act synergistically with multiple anti-myeloma agents. Our findings suggest that artesunate acts through iron to affect the mitochondria and induce low ROS and non-caspase–mediated apoptosis. Its potency, toxicity profile, and synergism with other drugs make it an intriguing new candidate for MM treatment.
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