Auranofin/Vitamin C: A Novel Drug Combination Targeting Triple-Negative Breast Cancer

Abstract

Background: Cancer cells from different origins exhibit various basal redox status and thus respond differently to intrinsic or extrinsic oxidative stress. These intricate characteristics condition the success of redox-based anticancer therapies that capitalize on the ability of reactive oxygen species to achieve selective and efficient cancer cell killing. Methods: Redox biology methods, SILAC (stable isotope labeling by amino acids in cell culture)-based proteomics and bioinformatics pattern comparisons were used to decipher the underlying mechanisms for differential response of lung and breast cancer cell models to redox-modulating molecule auranofin (AUF) and to combinations of AUF and vitamin C (VC). The in vivo effect of AUF, VC, and two AUF/VC combinations on mice bearing MDA-MB-231 xenografts (n = 5 mice per group) was also evaluated. All statistical tests were twosided. Results: AUF targeted simultaneously the thioredoxin and glutathione antioxidant systems. AUF/VC combinations exerted a synergistic and hydrogen peroxide (H2O2)-mediated cytotoxicity towards MDA-MB-231 cells and other breast cancer cell lines. The anticancer potential of AUF/VC combinations was validated in vivo on MDA-MB-231 xenografts in mice without notable side effects. On day 14 of treatments, mean tumor volumes for vehicletreated control group and the two AUF/VC combinations-treated groups (A/V1 and A/V2)were 197.67 ± 24.28, 15.66 ± 10.90 and 10.23 ± 7.30 mm 3 respectively, adjusted P values of the differences between mean tumor volumes of vehicle vs A/V1 groups and vehicle vs A/V2 groups were both less than .001. SILAC proteomics, bioinformatics analysis, and functional experiments linked prostaglandin reductase 1 (PTGR1) expression levels with breast cancer cell sensitivity to AUF/VC combinations. Conclusion:Combination of AUF and VC, two commonly available drugs, could be efficient against triple-negative breast cancer and potentially other cancers with similar redox properties and PTGR1 expression levels. Redox-based anticancer activity of this combination and the discriminatory potential of PTGR1 expression are worth further assessment in preclinical and clinical studies.

Therapeutic Use of Vitamin C in Cancer: Physiological Considerations

“…In combination, these molecules also act in a synergistic way, inducing extracellular production of H 2 O 2 and cytotoxicity against MDA-MB-231 (a breast cancer derived cell line) in cell culture and in xenografts in mice. Proteomic and functional analyses in this model suggested that prostaglandin reductase 1 expression was linked with the breast cancer sensitivity to AUF/AA combination (Hatem et al, 2018).…”

“…Experiments performed in vitro to test compatibility with other anti-carcinogenic substances revealed that AA can have a synergistic effect with some of them (Espey et al, 2011;Ma et al, 2014;Hatem et al, 2018;O'Leary et al, 2018;Graczyk-Jarzynka et al, 2019). For instance, Gemcitabine in combination with AA (Espey et al, 2011) have a synergistic cytotoxic effect in eight pancreatic cancer cell lines, which is mediated by the pro-oxidant effect of ascorbate, again with an increase in the production of H 2 O 2 .…”

“…A synergistic effect of AA and two of the chemotherapeutic drugs used in the treatment of ovarian cancer was also observed: carboplatin and paclitaxel, which inhibited tumor growth in models of mice with ovarian cancer and decreased the adverse effects of chemotherapy in patients with this disease. In triple negative breast cancer (TNBC), a new combination with AA was tested using Auranofin (AUF), which targets thioredoxin reductase (TRXR) (Hatem et al, 2018). In combination, these molecules also act in a synergistic way, inducing extracellular production of H 2 O 2 and cytotoxicity against MDA-MB-231 (a breast cancer derived cell line) in cell culture and in xenografts in mice.…”

Vitamin C versus Cancer: Ascorbic Acid Radical and Impairment of Mitochondrial Respiration?

“…Recent studies show that Cyb5R3/VDAC1 can activate bioreductive antitumor drugs, which in combination with vitamin C may affect mitochondrial activity, exhibiting additive or synergistic anticancer effects [17,79,80]. For example, vitamin C can sensitize cancer cells to redox-responsive chemotherapeutics (e.g., furanonaphtoquinones) after their bioreductive activation via Cyb5R3/VDAC1 [81,82].…”

Pro- and Antioxidant Effects of Vitamin C in Cancer in correspondence to Its Dietary and Pharmacological Concentrations

“…Vitamin C was shown to enhance the cytotoxic action against cancer cells in vitro and in mouse xenograft models exerted by auranofin, a redox-modulating drug targeting simultaneously thioredoxin and glutathione antioxidant systems [90]. Such combined action was efficient in triplenegative breast cancer and linked with the expression of prostaglandin reductase 1 (PTGR1).…”