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Artesunate overcomes drug resistance in multiple myeloma by inducing mitochondrial stress and non-caspase apoptosis

2014; Impact Journals LLC; Volume: 5; Issue: 12 Linguagem: Inglês

10.18632/oncotarget.1847

1949-2553

Xenofon Papanikolaou, Sadie Johnson, Tarun K. Garg, Erming Tian, Ruslana G. Tytarenko, Qing Zhang, Joshua Epstein, Bart Barlogie, Joshua Epstein, Christoph Heuck,

Cell death mechanisms and regulation

// Xenofon Papanikolaou 1 , Sarah Johnson 1 , Tarun Garg 1 , Erming Tian 1 , Ruslana Tytarenko 1 , Qing Zhang 1 , Caleb Stein 1 , Bart Barlogie 1 , Joshua Epstein 1 and Christoph Heuck 1 1 Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR Correspondence: Christoph Heuck, email: // Keywords : artesunate, apoptosis, caspases, myeloma, ROS Received : February 18, 2014 Accepted : March 22, 2014 Published : March 24, 2014 Abstract 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.