The Interrelationship of Pharmacologic Ascorbate Induced Cell Death and Ferroptosis
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Pharmacologic ascorbate induced cell death and ferroptosis share common features such as iron dependency, production of ROS, lipid peroxidation, caspase independency and the possible involvement of autophagy. These observations lead us to hypothesize that ferroptosis may also be involved in cancer cell death due to pharmacologic ascorbate treatment. Thus cell death of HT-1080 cell line was induced by ferroptosis inducers and pharmacologic ascorbate then the mechanism of cell death was compared. The EC50 value of pharmacologic ascorbate on HT-1080 cell line was found to be 0.5 mM that is in the range of the most ascorbate sensitive cell lines. However either of the specific inhibitors of ferroptosis (ferrostatin-1 and liproxstatin-1) could not elevate the viability of pharmacologic ascorbate treated cells suggesting that ferroptosis was not involved in the pharmacologic ascorbate induced cell death. α-tocopherol that could effectively elevate the viability of erastin and RSL3 treated HT1080 cells failed to mitigate the cytotoxic effect of pharmacologic ascorbate further strengthened this assumption. Furthermore at lower concentrations (0.1–0.5 mM) ascorbate could avoid the effects of ferroptosis inducers. Our results indicate that pharmacologic ascorbate induced cytotoxicity and ferroptosis – albeit phenotypically they show similar traits – are governed by different mechanisms.
KeywordsPharmacologic ascorbate Cell death ROS Lipid peroxidation Ferroptosis
We acknowledge Dr. Anita Sebestyén, of Semmelweis University Budapest for her generous gift of the HT-1080 cell line and Pál Gyulavári for his kind assistance for the FACSCalibur™ flow cytometer.
This work was financially supported by the National Research, Development and Innovation Fund of Hungary under Grant K 123752, 129593 by the BME-Biotechnology FIKP grant of EMMI and MedinProt Protein Excellence foundation.
Compliance with Ethical Standards
Conflicts of Interest
The authors declare no conflict of interest.
- 1.Tóth SZ, Lőrincz T, Szarka A (2017) Concentration does matter: The beneficial and potentially harmful effects of ascorbate in humans and plants. Antioxid Redox Signal 00:ars.2017.7125Google Scholar
- 11.Hong S-W, Jin D-H, Hahm E-S, Yim SH, Lim JS, Kim KI, Yang Y, Lee SS, Kang JS, Lee WJ, Lee WK, Lee MS (2007) Ascorbate (vitamin C) induces cell death through the apoptosis-inducing factor in human breast cancer cells. Oncol Rep 18:811–815Google Scholar
- 21.Sun X, Ou Z, Xie M et al (2015) HSPB1 as a novel regulator of ferroptotic cancer cell death. Oncogene:1–9Google Scholar
- 24.Lachaier E, Louandre C, Godin C, Saidak Z, Baert M, Diouf M, Chauffert B, Galmiche A (2014) Sorafenib induces ferroptosis in human cancer cell lines originating from different solid tumors. Anticancer Res 34:6417–6422Google Scholar
- 27.Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A, Eggenhofer E, Basavarajappa D, Rådmark O, Kobayashi S, Seibt T, Beck H, Neff F, Esposito I, Wanke R, Förster H, Yefremova O, Heinrichmeyer M, Bornkamm GW, Geissler EK, Thomas SB, Stockwell BR, O’Donnell VB, Kagan VE, Schick JA, Conrad M (2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 16:1180–1191CrossRefGoogle Scholar
- 33.Bocsi J, Nagy K, Tyihák E, Trézl L, Szende B (1998) Reduction of apoptosis of in vitro cultured lymphocytes of HIV-positive persons by N(G)-hydroxy-methylated-L-arginine and 1’-methyl-ascorbigen. Acta Biol Hung 49:331–337Google Scholar