High oxidative stress and DNA damage activity are increased

High oxidative stress and DNA damage activity are increased, while the anti-oxidant enzyme levels are decreased in MM patients (Mehdi et al., 2013). Several free radical drugs, such as As2O3 and ascorbic acid, have been used to treat MM, in which As2O3 generates ROS while ascorbic buy bepridil serves as an anti-oxidant agent. In MM preclinical and clinical studies, ascorbate was used as an adjunct drug and showed controversial results (Harvey et al., 2009; Perrone et al., 2009; Held et al., 2013; Sharma et al., 2012; Nakano et al., 2011; Takahashi, 2010; Sharma et al., 2009; Qazilbash et al., 2008). However, none of these tests used pharmacological doses of ascorbate and intravenous administration. It has been reported that ascorbate directly inactivates bortezomib activity by forming a tight but reversible complex through its vicinal diol group (Perrone et al., 2009; Harvey et al., 2009). This dose of ascorbate in the combination with bortezomib is at a physiological level which has anti-oxidant effect. We did not perform the combination of PAA with bortezomib due to a possible chemical reaction described above. However, our pilot study also suggested that PAA could overcome drug resistance to bortezomib in MM cells (data not shown). Our findings complement reported studies and further address the mechanism of action using clinical samples in which we observed that PAA killed tumor cells with high iron content, suggesting that iron might be the initiator of PAA cytotoxicity. In addition, combination of PAA with standard therapeutic drugs, such as melphalan, may significantly reduce the dose of melphalan needed. This is beneficial because high doses of melphalan are very toxic not only to tumor cells but also to normal tissues, such as hematopoietic stem cell and epithelial cells in the gut (Shaw et al., 2014; Bayraktar et al., 2013). The efficacy of high-dose melphalan by itself is clearly dose-dependent. Combined treatment of reduced dose melphalan with PAA achieved a significantly longer progression-free survival than the same dose of melphalan alone. These data also suggest that the bone marrow suppression induced by high-dose melphalan can be ameliorated by the combination of PAA with lower dose of melphalan because of the lack of toxicity of PAA on normal cells with low iron content. It is important to consider for future clinical studies that renal insufficiency could be a contraindication for usage of PAA in MM patients. Renal impairment is a common complication of MM (50%) and up to 5% require dialysis (Yadav et al., 2016a,b). The clinical toxicity is probably from oxalate, an end-product of ascorbate metabolism. Therefore, if creatinine clearance is <30mL/min, high dose ascorbic acid should be not administrated.
Funding Sources The data presented in this article were obtained at the Central Microscopy Research Facility, which is a Carver College of Medicine/Holden Comprehensive Cancer Center core research facility at the University of Iowa. The Facility is funded through user fees and the generous financial support of the Carver College of Medicine, Holden Comprehensive Cancer Center grant P30CA086862 and NIH grant 1S10RR018998-01. This work was also supported by NIH grants R01CA152105 (F.Z.), the Multiple Myeloma Research Foundation (F.Z.), the International Myeloma Foundation (F.Z.), the American Society of Hematology (ASH) Bridge (F.Z.), the UIHC-CCOM Research Investment Pilot Grants (F.Z.) and institutional start-up funds from the Department of Internal Medicine, Carver College of Medicine, University of Iowa (F.Z. and G.T.).
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Introduction The global increasing incidence of thyroid cancer in part attributed to improved diagnostic tools and surveillance has culminated in over-diagnosis and over-treatment (Vaccarella et al., 2016). The follicular variant of papillary thyroid carcinoma (FVPTC) is a heterogeneous group of tumors, including the infiltrating and encapsulated variants (Shi et al., 2016). The diagnosis of encapsulated FVPTC (EFVPTC) without invasion as a malignant lesion remains controversial (Hodak et al., 2016; Nikiforov et al., 2016; Thompson, 2016). The microscopic diagnostic criteria for EFVPTC are follicular architecture, widespread nuclear features of papillary carcinoma, some additional features (papillae, fibrous bands, dense eosinophilic colloid), and the presence of capsule (Shi et al., 2016).