Pharmacologic Ascorbate in Myeloma Treatment: Doses Matter

Ascorbic acid (vitamin C) has followed opaque paths in treating pharmacologic ascorbate. Because myeloma cells are iron-rich, increasmultiplemyeloma, and othermalignancies. Inmyeloma cells, ascorbate surprisingly depleted glutathione and potentiated arsenate trioxide efficacy. Because oral ascorbate at 1 g produces plasma saturation, this dose was selected with arsenate. Predictably, in small trials there was neither benefit nor harm (Rollig and Illmer, 2009; Parrow et al., 2013). Concurrently, the emerging proteasome inhibitor bortezomib was inhibited by ascorbate, which complexed with bortezomib's boron group. Despite inconsistencies (Perrone et al., 2009; Bannerman et al., 2011), concern remains about ascorbate-bortezomib interaction, and bortezomib is one of few agents that perhaps is ascorbate-inhibitable in vivo. Independently, pharmacologic ascorbate has become a promising chemotherapeutic agent in cancer treatment, but again following an opaque course (Parrow et al., 2013). Proposed as an anticancer treatment in 1954, and despite encouraging case documentation, ascorbate had no efficacy in two double-blind placebo-controlled trials. Ascorbate pharmacokinetics, from clinical studies on healthy subjects, explained why. Tight-control of ascorbate concentrations from oral ingestion, as in the double-blind trials, is by-passed by intravenous administration, as in the documented cases (Padayatty et al., 2004; Parrow et al., 2013). Only intravenous ascorbate at pharmacologic doses, (i.e., 1 g/kg) produces up to 25mMplasma and extracellular fluid concentrations, the latter serving as a pro-drug for extracellular H2O2 formation (Chen et al., 2008). With H2O2 +millimolar ascorbate, reactive oxygen species formed by Fenton-type reactions kill cancer but not normal cells. With proper patient screening, pharmacologic ascorbate has minimal risk (Padayatty et al., 2010). Many reports document efficacy of pharmacologic ascorbate in pre-clinical solid-tumor models and in phase I/early phase II trials. In this issue of EBioMedicine, Xia and colleagues use pharmacologic ascorbate in pre-clinical studies of myeloma (Xia et al., 2017). Advances presented included investigation ofmyeloma andnon-myelomahuman bone marrow cells from patients with myeloma; with smoldering myeloma; andwithmonoclonal gammopathy of uncertain significance. Iron homeostasis was characterized in bone marrow cells from several hundred patients, and findings were consistent with effects of