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

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.

Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis

“…, ferroptosis, based on its iron-dependence, ROS production, and caspase-independent cell death. Recent two reports also identified artesunate as a specific activator of ferroptosis, thus highlighting its potential to overcoming the resistance of cancer cells [21], [22].…”

“…Artesunate also induces lysosomal ROS-mediated mitochondrial apoptosis and targets the DNA damage and repair systems in conventional chemotherapeutic drug-resistant cancer cells [16], [17], [18], [19], [20]. Furthermore, a recent report suggested that artesunate induced iron-dependent, ROS-producing mitochondrial stress and non-caspase apoptosis [21]. Recently, artesunate was identified as a specific activator of a novel iron-dependent, caspase-independent, nonapoptotic ferroptosis that killed resistant cancer cells with oncogenic KRAS reprogramming [22].…”

“…Recently, artesunate was identified as a specific activator of a novel iron-dependent, caspase-independent, nonapoptotic ferroptosis that killed resistant cancer cells with oncogenic KRAS reprogramming [22]. Artesunate has been tested for its anticancer effects on various types of human malignancies but rarely using HNC cells [12], [14], [16], [17], [18], [19], [21], [23], [24], [25].…”

Stimulation of Suicidal Erythrocyte Death by Artesunate

“…Beyond that, artesunate is considered for the treatment of malignancy [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27]. Its efficacy in malignancy may at least in part result from its ability to induce tumor cell apoptosis [13,14,23,25,26,28,29,30,31]. The proapoptotic effect has been attributed in part to mitochondria [23,25,29].…”

“…Its efficacy in malignancy may at least in part result from its ability to induce tumor cell apoptosis [13,14,23,25,26,28,29,30,31]. The proapoptotic effect has been attributed in part to mitochondria [23,25,29]. Artemisinin, an antimalarial drug related to artesunate, has previously been reported to inhibit erythrocyte cation channels [32].…”