D-penicillamine combined with inhibitors of hydroperoxide metabolism enhances lung and breast cancer cell responses to radiation and carboplatin via H 2 O 2 -mediated oxidative stress

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 (100 μM) and copper sulfate (15 μM). 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.

Potential Anticancer Activity of Auranofin

“…The active sites of TrxR, -Cys-Val-Asn-Val-Gly-Cys-on the Nterminal side and -Gly-Cys-SeCys-Gly on the C-terminus, are essential for its enzyme activity. Because auranofin has high affinity for protein thiol and selenol groups, 20,68) it is thought that it binds the active sites of TrxR and inhibits its activity. Auranofin-induced inhibition of TrxR causes the accumulation of ROS in cells and induces apoptosis and cell death.…”

Effects of Qilin pills on spermatogenesis, reproductive hormones, oxidative stress, and the TSSK2 gene in a rat model of oligoasthenospermia

“…Antioxidant enzymes provide the first line of defense against the deleterious effects of ROS [45]. SOD catalyzes the dismutation of superoxide radicals to hydrogen peroxide (H 2 O 2 ) and molecular oxygen, whereas catalase (CAT) and glutathioneperoxidase (GSH-PX) are responsible for H 2 O 2 detoxification [46]. The decreased activity of SOD leads to the increased production of MDA via the catalytic cracking of lipid peroxides in the presence of metal ions.…”

Radiation-Drug Combinations to Improve Clinical Outcomes and Reduce Normal Tissue Toxicities: Current Challenges and New Approaches: Report of the Symposium Held at the 63rd Annual Meeting of the Radiation Research Society, 15–18 October 2017; Cancun, Mexico

“…Interestingly, cancer tissue has elevated copper levels when compared with normal tissue (37, 38). This elevated copper can interact with copper chelators such as D -penicillamine and disulfiram, causing induction of oxidative stress (39– 41). D-penicillamine is a repurposed drug that was previously used for treatment of Wilson’s disease and rheumatoid arthritis (41).…”

“…Disulfiram is used for the treatment of alcoholism (42). Both of these agents are now being investigated as anti-cancer drugs and have shown promise when combined with both chemotherapy and radiation (39, 43, 44). Notably, studies have shown that disulfiram is safe and tolerable in patients treated for both glioblastoma and NSCLC in combination with standard chemotherapies (43, 44).…”