Abstract
The discovery of artemisinin (ART) for malaria treatment won the 2015 Nobel Prize in Medicine, which inspired the rediscovery and development of ART for the treatment of other diseases including cancer. In this study, we investigated the potential therapeutic effect of ART and dihydroartemisinin (DHA) on multiple myeloma (MM) cells including primary MM cells and in 5TMM3VT mouse model. Both in vitro and in vivo experiments showed that DHA might be a more promising anti-MM agent with significantly improved efficacy compared to ART. Mechanistic analyses suggested that DHA activated the mitochondrial apoptotic pathway by interacting with ferrous (Fe2+) ions and oxygen to produce reactive oxygen species (ROS). Intriguingly, DHA could reverse the upregulated expression of B-cell lymphoma 2 (Bcl-2) protein, a typical mitochondrial apoptotic marker, induced by dexamethasone (Dexa) in MM. We further demonstrated that DHA treatment could overcome Dexa resistance and enhance Dexa efficacy in MM. Additionally, DHA combined with Dexa resulted in increased ROS production and cytochrome C translocation from the mitochondria to the cytoplasm, resulting in alterations to the mitochondrial membrane potential and caspase-mediated apoptosis. In summary, our study demonstrated that DHA was superior to ART in MM treatment and overcame Dexa resistance both in vitro and in vivo, providing a promising therapeutic strategy for MM therapy.
Highlights
Multiple myeloma (MM) remains an incurable hematological malignancy of plasma cells, despite the therapeutic advances over the past two decades with numerous agents including proteasome inhibitors such as bortezomib [1], ixazomib [2], and carfilzomib [3], monoclonal antibodies such as elotuzumab [4], and daratumumab [5], immunomodulatory drugs such as pomalidomide [6] and lenalidomide [7], and other treatments including chimeric antigen receptors (CAR)-T-cell therapy [8, 9] gaining clinical approval
Examples of this include DHA combined with gemcitabine, which is efficacious against pancreatic tumor cells by suppressing gemcitabine-induced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation [22]; DHA combined with cyclophosphamide, which inhibits spontaneous pulmonary metastasis [23], and a combination of DHA and gemcitabine, which decreases hepatoma tumor growth [24]
Irrespective of the concentration of Dexa used, the combination treatment restored the Dexa-induced B-cell lymphoma 2 (Bcl-2) expression in the resistant cells, suggesting that DHA treatment was able to overcome Dexa resistance. These results show that the cytotoxic effects of DHA combined with Dexa were mediated by increased reactive oxygen species (ROS) production, altering ψm, reversing changes to Bcl-2 expression mediated by Dexa, increasing release of mitochondrial cytochrome C (Cyt C), activating caspase-3, and inducing caspase-mediated apoptosis
Summary
Multiple myeloma (MM) remains an incurable hematological malignancy of plasma cells, despite the therapeutic advances over the past two decades with numerous agents including proteasome inhibitors such as bortezomib [1], ixazomib [2], and carfilzomib [3], monoclonal antibodies such as elotuzumab [4], and daratumumab [5], immunomodulatory drugs such as pomalidomide [6] and lenalidomide [7], and other treatments including chimeric antigen receptors (CAR)-T-cell therapy [8, 9] gaining clinical approval. In lung cancer, DHA-inhibited proliferation induces cell cycle arrest and decreases tumor growth by suppressing invasion and migration, increases the concentration of calcium (Ca2+) ions, and activates p38 [19]. Artemisinin-type drugs increase the sensitivity of resistant cancer cells to conventional drugs [21]. Examples of this include DHA combined with gemcitabine, which is efficacious against pancreatic tumor cells by suppressing gemcitabine-induced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation [22]; DHA combined with cyclophosphamide, which inhibits spontaneous pulmonary metastasis [23], and a combination of DHA and gemcitabine, which decreases hepatoma tumor growth [24]. The synergistic effects of DHA with the conventional drug Dexa for the treatment of MM have not yet been determined
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