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D-penicillamine combined with inhibitors of hydroperoxide metabolism enhances lung and breast cancer cell responses to radiation and carboplatin via H2O2-mediated oxidative stress
Journal article   Open access   Peer reviewed

D-penicillamine combined with inhibitors of hydroperoxide metabolism enhances lung and breast cancer cell responses to radiation and carboplatin via H2O2-mediated oxidative stress

Sebastian J Sciegienka, Shane R Solst, Kelly C Falls, Joshua D Schoenfeld, Adrienne R Klinger, Natalie L Ross, Samuel N Rodman, Douglas R Spitz and Melissa A Fath
Free radical biology & medicine, Vol.108, pp.354-361
07/2017
DOI: 10.1016/j.freeradbiomed.2017.04.001
PMCID: PMC5495544
PMID: 28389407
url
https://www.ncbi.nlm.nih.gov/pmc/articles/5495544View
Open Access

Abstract

D-penicillamine (DPEN), a copper chelator, has been used in the treatment of Wilson's disease, cystinuria, and rheumatoid arthritis. Recent evidence suggests that DPEN in combination with biologically relevant copper (Cu) concentrations generates H2O2 in cancer cell cultures, but the effects of this on cancer cell responses to ionizing radiation and chemotherapy are unknown. Increased steady-state levels of H2O2 were detected in MB231 breast and H1299 lung cancer cells following treatment with DPEN (100µM) and copper sulfate (15µM). Clonogenic survival demonstrated that DPEN-induced cancer cell toxicity was dependent on Cu and was significantly enhanced by depletion of glutathione [using buthionine sulfoximine (BSO)] as well as inhibition of thioredoxin reductase [using Auranofin (Au)] prior to exposure. Treatment with catalase inhibited DPEN toxicity confirming H2O2 as the toxic species. Furthermore, pretreating cancer cells with iron sucrose enhanced DPEN toxicity while treating with deferoxamine, an Fe chelator that inhibits redox cycling, inhibited DPEN toxicity. Importantly, DPEN also demonstrated selective toxicity in human breast and lung cancer cells, relative to normal untransformed human lung or mammary epithelial cells and enhanced cancer cell killing when combined with ionizing radiation or carboplatin. Consistent with the selective cancer cell toxicity, normal untransformed human lung epithelial cells had significantly lower labile iron pools than lung cancer cells. These results support the hypothesis that DPEN mediates selective cancer cell killing as well as radio-chemo-sensitization by a mechanism involving metal ion catalyzed H2O2-mediated oxidative stress and suggest that DPEN could be repurposed as an adjuvant in conventional cancer therapy. [Display omitted] •DPEN+Cu at physiologic concentrations increase H2O2 levels in cancer cells.•DPEN's clonogenic toxicity is enhanced using auranofin and buthionine sulfoximine.•DPEN+Cu treatment is more toxic to cancer cells than to normal epithelial cells.•DPEN toxicity in correlated with intracellular labile iron pools.•Labile iron pools are higher in cancer cells verses normal lung epithelial cells.
 Breast cancer Hydrogen peroxide Transition metal ions Oxidative metabolism Lung cancer D-penicillamine

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