Iron‐dependent cell death of hepatocellular carcinoma cells exposed to sorafenib
Abstract
The multikinase inhibitor sorafenib is currently the treatment of reference for advanced hepatocellular carcinoma (HCC). In our report, we examined the cytotoxic effects of sorafenib on HCC cells. We report that the depletion of the intracellular iron stores achieved by using the iron chelator deferoxamine (DFX) strikingly protects HCC cells from the cytotoxic effects of sorafenib. The protective effect of the depletion of intracellular iron stores could not be explained by an interference with conventional forms of programmed cell death, such as apoptosis or autophagic cell death. We also found that DFX did not prevent sorafenib from reaching its intracellular target kinases. Instead, the depletion of intracellular iron stores prevented sorafenib from inducing oxidative stress in HCC cells. We examined the possibility that sorafenib might exert a cytotoxic effect that resembles ferroptosis, a form of cell death in which iron‐dependent oxidative mechanisms play a pivotal role. In agreement with this possibility, we found that pharmacological inhibitors (ferrostatin‐1) and genetic procedures (RNA interference against IREB‐2) previously reported to modulate ferroptosis, readily block the cytotoxic effects of sorafenib in HCC cells. Collectively, our findings identify ferroptosis as an effective mechanism for the induction of cell death in HCC. Ferroptosis could potentially become a goal for the medical treatment of HCC, thus opening new avenues for the optimization of the use of sorafenib in these tumors.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In HCC cell lines, sorafenib induces non-apoptotic death that lipophilic antioxidants suppress, indicating sorafenib activates ferroptosis.
“In HCC cell lines, sorafenib was reported to induce a non-apoptotic form of cell death that was suppressed by lipophilic antioxidants [27, 28], indicating that sorafenib activates ferroptosis in HCC cell lines.”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [27]
Cites
Sorafenib in advanced hepatocellular carcinoma
Llovet, J. M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J.-F., de Oliveira, A. C., Santoro, A., Raoul, J.-L., Forner, A., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0708857 · Cited by 13,097 · see citing works
Valko, M., Morris, H., Mazúr, M., Rapta, P., & Bilton, R. F. (2001) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/s0304-4165(01)00163-5 · Cited by 124 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition
Doll, S., Proneth, B., Tyurina, Y. Y., Panzilius, E., Kobayashi, S., Ingold, I., Irmler, M., Beckers, J., Aichler, M., Walch, A., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2239 · Cited by 4,293 · see citing works
Ferroptosis: process and function
Xie, Y., Hou, W., Song, X., Yu, Y., Huang, J., Sun, X., Kang, R., & Tang, D. (2016) · Cell Death & Differentiation · doi:10.1038/cdd.2015.158 · Cited by 3,727 · see citing works
Ferroptosis: Death by Lipid Peroxidation
Yang, W. S., & Stockwell, B. R. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.10.014 · Cited by 3,088 · see citing works
Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis
Yang, W. S., Kim, K. J., Gaschler, M. M., Patel, M., Shchepinov, M. S., & Stockwell, B. R. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1603244113 · Cited by 2,329 · see citing works
ROS in cancer therapy: the bright side of the moon
Perillo, B., Di Donato, M., Pezone, A., Di Zazzo, E., Giovannelli, P., Galasso, G., Castoria, G., & Migliaccio, A. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-0384-2 · Cited by 2,176 · see citing works
Dixon, S. J., Patel, D. N., Welsch, M., Skouta, R., Lee, E. D., Hayano, M., Thomas, A. G., Gleason, C. E., Tatonetti, N. P., Slusher, B. S., et al. (2014) · eLife · doi:10.7554/elife.02523 · Cited by 2,088 · see citing works
Sun, X., Ou, Z., Chen, R., Niu, X., Chen, D., Kang, R., & Tang, D. (2016) · Hepatology · doi:10.1002/hep.28251 · Cited by 2,012 · see citing works
Role of GPX4 in ferroptosis and its pharmacological implication
Seibt, T. M., Proneth, B., & Conrad, M. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.09.014 · Cited by 1,520 · see citing works
Cao, J. Y., & Dixon, S. J. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2194-1 · Cited by 1,515 · see citing works
Ferroptosis: Mechanisms and links with diseases
Yan, H.-F., Zou, T., Tuo, Q.-Z., Xu, S., Li, H., Belaidi, A. A., & Lei, P. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00428-9 · Cited by 1,471 · see citing works
The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity
Xie, Y., Zhu, S., Song, X., Sun, X., Fan, Y., Liu, J., Zhong, M., Yuan, H., Zhang, L., Billiar, T. R., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.07.055 · Cited by 952 · see citing works
The emerging role of ferroptosis in inflammation
Sun, Y., Chen, P., Zhai, B., Zhang, M., Xiang, Y., Fang, J., Xu, S., Gao, Y., Chen, X., Sui, X., et al. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110108 · Cited by 739 · see citing works
RSL3 Drives Ferroptosis Through GPX4 Inactivation and ROS Production in Colorectal Cancer
Sui, X., Zhang, R., Liu, S., Duan, T., Zhai, L., Zhang, M., Han, X., Xiang, Y., Huang, X., Lin, H., et al. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01371 · Cited by 703 · see citing works
Regulated necrosis: disease relevance and therapeutic opportunities
Conrad, M., Angeli, J. P. F., Vandenabeele, P., & Stockwell, B. R. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.6 · Cited by 630 · see citing works
From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy
Efferth, T. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.02.009 · Cited by 632 · see citing works
Regulation of lipid peroxidation and ferroptosis in diverse species
Conrad, M., Kagan, V. E., Bayir, H., Pagnussat, G. C., Head, B., Traber, M. G., & Stockwell, B. R. (2018) · Genes & Development · doi:10.1101/gad.314674.118 · Cited by 544 · see citing works
The application of Ferroptosis in diseases
Qiu, Y., Cao, Y., Cao, W., Jia, Y., & Lu, N. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.104919 · Cited by 415 · see citing works
Artemisinin derivatives induce iron-dependent cell death (ferroptosis) in tumor cells
Ooko, E., Saeed, M. E. M., Kadioglu, O., Sarvi, S., Colak, M., Elmasaoudi, K., Janah, R., Greten, H. J., & Efferth, T. (2015) · Phytomedicine · doi:10.1016/j.phymed.2015.08.002 · Cited by 387 · see citing works
Louandre, C., Marcq, I., Bouhlal, H., Lachaier, E., Godin, C., Saidak, Z., François, C., Chatelain, D., Debuysscher, V., Barbare, J.-C., et al. (2015) · Cancer Letters · doi:10.1016/j.canlet.2014.11.014 · Cited by 374 · see citing works
Self-citationUnraveling the Potential Role of Glutathione in Multiple Forms of Cell Death in Cancer Therapy
Lv, H., Zhen, C., Liu, J., Yang, P., Hu, L., & Shang, P. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/3150145 · Cited by 320 · see citing works
Liver stage malaria infection is controlled by host regulators of lipid peroxidation
Kain, H. S., Glennon, E. K. K., Vijayan, K., Arang, N., Douglass, A. N., Fortin, C. L., Zuck, M., Lewis, A. J., Whiteside, S. L., Dudgeon, D. R., et al. (2020) · Cell Death & Differentiation · doi:10.1038/s41418-019-0338-1 · Cited by 91 · see citing works
NUPR1 inhibitor ZZW-115 induces ferroptosis in a mitochondria-dependent manner
Huang, C., Santofimia-Castaño, P., Liu, X., Xia, Y., Peng, L., Gotorbe, C., Neira, J. L., Tang, D., Pouyssegur, J., & Iovanna, J. (2021) · Cell Death Discovery · doi:10.1038/s41420-021-00662-2 · Cited by 76 · see citing works
- Authors
- Louandre, C., Ezzoukhry, Z., Godin, C., Barbare, J., Mazière, J., Chauffert, B., & Galmiche, A.
- Affiliations
- Inserm (FR)
- Centre Hospitalier Universitaire Amiens-Picardie (FR)
- Corresponding author
- Galmiche, Antoine
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2013-04-08
- Volume
- 133
- Issue
- 7
- Pages
- 1732-1742
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- OpenAlex
- W1513392008
- Cited by
- 602
- References
- 2
- Citations by year
- 2026: 50 · 2025: 51 · 2024: 77 · 2023: 87 · 2022: 100 · 2021: 78 · 2020: 59 · 2019: 28 · 2018: 22 · 2017: 19 · 2016: 15 · 2015: 10 · 2014: 6
- FWCI
- 8.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- sorafenib, hepatocellular carcinoma, ferroptosis, iron depletion, deferoxamine, oxidative stress, ferrostatin-1, multikinase inhibitor, apoptosis, autophagic cell death, drug resistance
- MeSH terms
- Sorafenib, Antineoplastic Agents, Cell Survival, Cyclohexylamines, Deferoxamine, Carcinoma, Hepatocellular, Humans, Iron, Liver Neoplasms, Niacinamide, Phenylenediamines, Phenylurea Compounds, Cell Death, Siderophores, Oxidative Stress, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, RNA Interference, Iron Regulatory Protein 2, Cell Line, Tumor, Protein Kinase Inhibitors, Extracellular Signal-Regulated MAP Kinases, raf Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
