Research ArticleExperimental Studies
Open Access

Sulfasalazine an Inhibitor of System xC− (Cystine/glutamate Antiporter), Combined With Recombinant Methioninase, Inhibits Both Cancer and Normal Cells, Suggesting Lack of Cancer Selectivity of Cysteine Restriction

JINSOO KIM, QINGHONG HAN, SHUKUAN LI, BYUNG MO KANG, YUTA MIYASHI, TOMOYUKI ISHIGURO, MICHAEL BOUVET and ROBERT M. HOFFMAN
Anticancer Research May 2026, 46 (5) 2353-2359; DOI: https://doi.org/10.21873/anticanres.18122

Abstract

Background/Aim: Sulfasalazine (SSZ), an inhibitor of xCT/system xC−, blocks cystine uptake and depletes intracellular glutathione, leading to ferroptotic cell death. Recombinant methioninase (rMETase) targets methionine addiction of cancer inhibits cancer growth, and enhances the efficacy of chemotherapy. Targeting the cysteine and methionine metabolism pathways together may effect synergistic efficacy. The present study determined whether SSZ combined with rMETase results in cancer-selective efficacy compared with normal cells.

Materials and Methods: The half-maximal inhibitory concentrations (IC50) of SSZ and rMETase were each determined on HCT116 human colon-cancer cells and Hs-27 human normal fibroblasts in vitro. Viability of HCT116 and Hs-27 cells treated with SSZ alone, rMETase alone, or the combination of SSZ and rMETase was determined with the WST-8 viability reagent.

Results: SSZ had similar IC50 values on HCT116 cancer cells and Hs-27 normal fibroblasts (1.25 mM vs. 1.11 mM, respectively). In contrast, rMETase had higher efficacy on HCT116 colon-cancer cells (IC50=0.33 U/ml) than on Hs-27 fibroblasts (IC50=0.55 U/ml), indicating greater sensitivity of cancer cells. The combination of SSZ and rMETase significantly reduced cell viability compared with untreated control, SSZ alone, and rMETase alone, on both HCT116 and Hs-27 cells (each comparison, all p<0.05), demonstrating that the enhanced efficacy of SSZ under methionine restriction is not cancer-selective.

Conclusion: SSZ shows comparable growth inhibition in cancer and normal cells and displays enhanced efficacy in combination with rMETase on both cell types. These findings suggest that cysteine restriction, unlike methionine restriction, is not a cancer-specific vulnerability.

Keywords:

Introduction

Cysteine is closely linked to redox homeostasis. Many cells acquire intracellular cysteine mainly through xCT (SLC7A11), which is a system xC− (cystine/glutamate antiporter), followed by intracellular reduction of cystine to cysteine which is used for protein and glutathione synthesis and antioxidant defense (1, 2). Sulfasalazine (SSZ), a clinically-used anti-inflammatory drug, inhibits the xCT/system xC− and can compromise redox homeostasis by restricting cysteine availability (3).

Methionine addiction is a fundamental and general metabolic hallmark of cancer, known as the Hoffman effect (4-21). Methionine addiction is due at least in part to enhanced transmethylation reactions, causing cancer cells to become increasingly reliant on exogenous methionine. Therefore, methionine addiction of cancer has been therapeutically targeted by methionine restriction, including both by low-methionine diets and by recombinant methioninase (rMETase). rMETase enzymatically degrades extracellular methionine and has been widely used to effect methionine restriction, which frequently results in synergistic efficacy when combined with numerous chemotherapy drugs on cancer cells in contrast to normal cells (4-21).

Because the cysteine and methionine metabolic pathways are tightly linked and functionally connected (22), combining restriction of cysteine and methionine may enhance growth inhibition of cancer (23, 24). However, a major question is whether such a strategy is cancer-selective.

The present study determined whether combining SSZ and rMETase produces cancer-selective or non-selective growth inhibition on HCT116 colon-cancer cells compared to Hs-27 normal fibroblasts.

Materials and Methods

Cell culture. HCT116 human colon-cancer cells and Hs-27 human normal fibroblasts were obtained from the American Type Culture Collection (Manassas, VA, USA). The cells were maintained in Dulbecco’s Modified Eagle’s Medium/Nutrient Mixture F-12 with GlutaMAX™ supplement (DMEM/F-12; Thermo Fisher Scientific, Waltham, MA, USA) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin at 37°C in a humidified atmosphere containing 5% CO2.

Reagents. SSZ was purchased from Tocris Bioscience (Bristol, UK) and dissolved in dimethyl sulfoxide at a stock concentration of 100 mM.

Recombinant methioninase (rMETase) production. rMETase was produced by AntiCancer Inc. (San Diego, CA, USA) by fermenting Escherichia coli transformed with the Pseudomonas putida methioninase gene. Methioninase was purified by heat treatment at 60°C, polyethylene glycol precipitation, and diethylaminoethyl (DEAE) Sepharose ion-exchange chromatography as previously described (10).

SSZ and rMETase sensitivity assays. HCT116 colon-cancer cells and Hs-27 normal fibroblasts were seeded at 2.0×103 cells per well in 96-well plates and incubated overnight in Dulbecco’s Modified Eagle’s medium/FIZ with 10% fetal bovine serum. The next day, cells were treated for 72 h with increasing concentrations of SSZ (0.0625~4 mM) or rMETase (0.125~8 U/ml). Cell viability was assessed using the Cell Counting Kit-8 (Dojindo Laboratories, Kumamoto, Japan) containing the WST-8 cell-viability reagent. Ten microliters of WST-8 solution were added to each well, followed by a 1 h incubation at 37°C. Absorbance was then measured at 450 nm using a microplate reader (Sunrise; Tecan, Männedorf, Switzerland). Cell viability was calculated as a percentage of treated cells relative to that of untreated control cells. Drug-sensitivity curves and half-maximal inhibitory concentration (IC50) values were generated using Microsoft 365 Excel for MacOS (Microsoft, Redmond, WA, USA), ImageJ version 1.54g (National Institutes of Health, Bethesda, MD, USA), and GraphPad Prism version 10.6.1 (GraphPad Software, Inc., San Diego, CA, USA).

Combination treatment with SSZ and rMETase of HCT-116 colon cancer cells and Hs27 normal fibroblasts. HCT116 colon-cancer cells and Hs-27 normal fibroblasts were seeded in 96-well plates at a density of 2.0×103 cells/well in Dulbecco’s modified Eagle’s medium/F-12 with 10% fetal bovine serum. After 24 h, the cells were treated for 72 h with SSZ and rMETase, each administered at its respective IC50 concentration (as determined for the corresponding cell line), either each agent alone or in combination. Cell viability was then determined as described above. Each experimental condition was tested in multiple replicate wells and repeated in six independent experiments (n=6).

Statistical analysis. Dose–response curves were fitted using a four-parameter logistic model with nonlinear regression. Data are presented as the mean±standard deviation. Comparisons between groups were performed using one-way analysis of variance. Statistical significance was determined using Dunnett’s multiple comparison test, with values of p≤0.05 considered significant.

Results

Determination of IC50 values of SSZ and rMETase on HCT116 colon-cancer cells and Hs-27 normal fibroblasts. SSZ had similar growth inhibition οn cancer and normal cells. SSZ decreased cell viability in a concentration-dependent manner on both HCT116 cancer cells and Hs-27 normal fibroblasts (Figure 1). The IC50 values of normal and cancer cells were similar between the two cell types (1.25 mM on HCT116 and 1.11 mM on Hs-27), suggesting lack of cancer selectivity of SSZ-mediated cysteine restriction in vitro. rMETase also reduced cell viability in a concentration-dependent manner on both cell types (Figure 2). HCT116 cancer cells were more sensitive to rMETase than Hs-27 fibroblasts, with IC50 values of 0.33 U/ml and 0.55 U/ml, respectively. These results indicate that rMETase has greater efficacy on HCT116 cancer cells than Hs-27 normal fibroblasts.

Figure 1.
Figure 1.

Dose–response of SSZ on the viability of HCT116 colon-cancer cells and Hs-27 normal fibroblasts. Values of half-maximal inhibitory concentration (IC50) were determined by nonlinear regression using a four-parameter logistic model. Data are shown as the mean±standard deviation. SSZ: Sulfasalazine.

Figure 2.
Figure 2.

Dose–response of rMETase on HCT116 colon-cancer cells and Hs-27 normal fibroblasts. Values of half-maximal inhibitory concentration (IC50) were determined by nonlinear regression using a four-parameter logistic model. Data are shown as the mean±standard deviation. rMETase: Recombinant methioninase.

Efficacy of the combination of SSZ and rMETase on HCT116 colon-cancer cells and Hs-27 normal fibroblasts. At IC50 concentrations, SSZ alone and rMETase alone significantly reduced viability compared with untreated controls of both HCT116 cancer cells and Hs-27 normal fibroblasts (Figure 3A and 3B). The combination of SSZ and rMETase further reduced viability compared with untreated controls, SSZ alone, and rMETase alone on both HCT116 colon-cancer cells and Hs-normal fibroblasts (all pairwise comparisons, p<0.05, as indicated by asterisks in Figures 3 A and B). Thus, the enhanced growth inhibition by adding SSZ under methionine restriction occurred not only on cancer cells but also on normal fibroblasts, indicating that cysteine restriction is not a cancer-specific vulnerability.

Figure 3.
Figure 3.

SSZ plus recombinant methioninase reduced viability more than either single agent on both cancer and normal cells. (A) HCT116 colon-cancer cells and (B) Hs-27 normal fibroblasts were treated with SSZ alone, rMETase alone, or SSZ plus rMETase at their respective IC50 concentrations. Data are shown as mean±SD. *p≤0.05 for combination vs. SSZ; combination vs. rMETase; and combination vs. control. rMETase: Recombinant methioninase; SSZ: sulfasalazine.

Discussion

The present study compared the efficacy of combining SSZ, an inhibitor of cellular cystine uptake with rMETase on HCT116 colon-cancer cells and Hs-27 normal fibroblasts. SSZ alone had similar IC50 values on HCT116 colon-cancer cells and Hs-27 normal fibroblasts, suggesting lack of cancer selectivity of SSZ-induced cystine restriction under the present conditions. In contrast, rMETase was more potent on HCT116 than on Hs-27 cells, consistent with the greater sensitivity of cancer cells to methionine restriction (4-21).

The major finding of the present study is that rMETase enhanced the efficacy of SSZ similarly on both cancer and normal cells. In previous studies, rMETase selectively increased the activity of multiple anticancer agents on cancer cells, whereas such synergy was not observed on Hs-27 normal fibroblasts (16-21).

In the present study, the SSZ plus rMETase combination produced a significantly greater reduction in viability than untreated control, SSZ alone, and rMETase alone on both HCT116 colon-cancer cells and Hs-27 normal fibroblasts. Therefore, unlike rMETase combinations with chemotherapy drugs, the rMETase plus SSZ combination is not cancer-specific.

Cysteine availability is linked to redox homeostasis because many cells depend on xCT (SLC7A11)/system xC−-mediated cystine uptake to sustain intracellular cysteine and glutathione synthesis as well as protein synthesis (1, 2). SSZ inhibits the xCT/system xC− and can compromise antioxidant capacity by restricting cysteine availability (22).

Methionine restriction may further reduce cellular tolerance to metabolic and oxidative stress, thereby amplifying the inhibitory effect of SSZ (23, 24). Because normal fibroblasts also rely on these pathways, the combination of SSZ and rMETase can impose a shared metabolic stress on both cancer and normal cells rather than exploiting a cancer-specific vulnerability.

In conclusion, rMETase alone showed greater efficacy in HCT116 colon-cancer cells than on Hs-27 normal fibroblasts. However, rMETase increased SSZ efficacy on both HCT116 colon-cancer and Hs-27 normal fibroblasts. The present results indicate that cysteine restriction via SSZ, even when combined with methionine restriction, is not a cancer-specific vulnerability despite numerous studies claiming the contrary (24-27). Our previous study also showed cysteine restriction is not a cancer-specific vulnerability, unlike methionine restriction (28).

Methionine restriction is showing clinical promise (10, 11, 12, 29, 30).

Acknowledgements

This article is dedicated to the memory of A.R. Moossa, MD; Sun Lee, MD; Professor Philip Miles; Richard W. Erbe, MD; Professor Milton Plesur; Professor Gordon H. Sato; Professor Li Jiaxi; Masaki Kitajima, MD; Shigeo Yagi, Ph.D.; Jack Geller, MD; Joseph R Bertino, MD; J.A.R. Mead, Ph.D.; Eugene P. Frenkel, MD; John Medelsohn, MD; Professor Lev Bergelson; Professor Sheldon Penman; Professor John R. Raper; Professor Peter H. Duelseng; Professor J.D. Watson; and Joseph Leighton, MD. May their memory be a blessing.

The Robert M. Hoffman Foundation for Cancer Research provided funds for the present study.

Footnotes

  • Authors’ Contributions

    JK and RMH designed the study. QH and SL produced rMETase. JK conducted all experiments and wrote the article. RMH revised the article. BMK, YM, TI, and MB critically read the manuscript.

  • Conflicts of Interest

    None of the Authors has conflicts of interest or financial ties to disclose related to this study.

  • Artificial Intelligence (AI) Disclosure

    No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.

  • Received January 8, 2026.
  • Revision received March 1, 2026.
  • Accepted March 2, 2026.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

References

  1. ↵
    1. Bannai S
    : Exchange of cystine and glutamate across plasma membrane of human fibroblasts. J Biol Chem 261(5): 2256-2263, 1986.
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Bridges RJ,
    2. Natale NR,
    3. Patel SA
    : System xc− cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS. Br J Pharmacol 165(1): 20-34, 2012. DOI: 10.1111/j.1476-5381.2011.01480.x
    OpenUrlCrossRefPubMed
  3. ↵
    1. Gout PW,
    2. Buckley AR,
    3. Simms CR,
    4. Bruchovsky N
    : Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the xc − cystine transporter: a new action for an old drug. Leukemia 15(10): 1633-1640, 2001. DOI: 10.1038/sj.leu.2402238
    OpenUrlCrossRefPubMed
  4. ↵
    1. Hoffman RM,
    2. Erbe RW
    : High in vivo rates of methionine biosynthesis in transformed human and malignant rat cells auxotrophic for methionine. Proc Natl Acad Sci U S A 73(5): 1523-1527, 1976. DOI: 10.1073/pnas.73.5.1523
    OpenUrlAbstract/FREE Full Text
    1. Coalson DW,
    2. Mecham JO,
    3. Stern PH,
    4. Hoffman RM
    : Reduced availability of endogenously synthesized methionine for S-adenosylmethionine formation in methionine-dependent cancer cells. Proc Natl Acad Sci U S A 79(14): 4248-4251, 1982. DOI: 10.1073/pnas.79.14.4248
    OpenUrlAbstract/FREE Full Text
    1. Stern PH,
    2. Mecham JO,
    3. Wallace CD,
    4. Hoffman RM
    : Reduced free-methionine in methionine-dependent SV40-transformed human fibroblasts synthesizing apparently normal amounts of methionine. J Cell Physiol 117(1): 9-14, 1983. DOI: 10.1002/jcp.1041170103
    OpenUrlCrossRefPubMed
    1. Judde JG,
    2. Ellis M,
    3. Frost P
    : Biochemical analysis of the role of transmethylation in the methionine dependence of tumor cells. Cancer Res 49(17): 4859-4865, 1989.
    OpenUrlAbstract/FREE Full Text
    1. Stern PH,
    2. Hoffman RM
    : Elevated overall rates of transmethylation in cell lines from diverse human tumors. In Vitro 20(8): 663-670, 1984. DOI: 10.1007/BF02619617
    OpenUrlCrossRefPubMed
    1. Yamamoto J,
    2. Aoki Y,
    3. Inubushi S,
    4. Han Q,
    5. Hamada K,
    6. Tashiro Y,
    7. Miyake K,
    8. Matsuyama R,
    9. Bouvet M,
    10. Clarke SG,
    11. Endo I,
    12. Hoffman RM
    : Extent and instability of trimethylation of histone H3 lysine increases with degree of malignancy and methionine addiction. Cancer Genomics Proteomics 19(1): 12-18, 2022. DOI: 10.21873/cgp.20299
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Tan Y,
    2. Xu M,
    3. Tan X,
    4. Tan X,
    5. Wang X,
    6. Saikawa Y,
    7. Nagahama T,
    8. Sun X,
    9. Lenz M,
    10. Hoffman RM
    : Overexpression and large-scale production of recombinantl-methionine-α-deamino-γ-mercaptomethane-lyase for novel anticancer therapy. Protein Expr Purif 9(2): 233-245, 1997. DOI: 10.1006/prep.1996.0700
    OpenUrlCrossRefPubMed
  11. ↵
    1. Epner DE,
    2. Morrow S,
    3. Wilcox M,
    4. Houghton JL
    : Nutrient intake and nutritional indexes in adults with metastatic cancer on a phase I clinical trial of dietary methionine restriction. Nutr Cancer 42(2): 158-166, 2002. DOI: 10.1207/S15327914NC422_2
    OpenUrlCrossRefPubMed
  12. ↵
    1. Durando X,
    2. Farges MC,
    3. Buc E,
    4. Abrial C,
    5. Petorin-Lesens C,
    6. Gillet B,
    7. Vasson MP,
    8. Pezet D,
    9. Chollet P,
    10. Thivat E
    : Dietary methionine restriction with FOLFOX regimen as first line therapy of metastatic colorectal cancer: a feasibility study. Oncology 78(3-4): 205-209, 2010. DOI: 10.1159/000313700
    OpenUrlCrossRefPubMed
    1. Yamamoto J,
    2. Han Q,
    3. Inubushi S,
    4. Sugisawa N,
    5. Hamada K,
    6. Nishino H,
    7. Miyake K,
    8. Kumamoto T,
    9. Matsuyama R,
    10. Bouvet M,
    11. Endo I,
    12. Hoffman RM
    : Histone methylation status of H3K4me3 and H3K9me3 under methionine restriction is unstable in methionine-addicted cancer cells, but stable in normal cells. Biochem Biophys Res Commun 533(4): 1034-1038, 2020. DOI: 10.1016/j.bbrc.2020.09.108
    OpenUrlCrossRefPubMed
    1. Raboni S,
    2. Montalbano S,
    3. Stransky S,
    4. Garcia BA,
    5. Buschini A,
    6. Bettati S,
    7. Sidoli S,
    8. Mozzarelli A
    : A key silencing histone mark on chromatin is lost when colorectal adenocarcinoma cells are depleted of methionine by methionine γ-lyase. Front Mol Biosci 8: 735303, 2021. DOI: 10.3389/fmolb.2021.735303
    OpenUrlCrossRefPubMed
    1. Abo Qoura L,
    2. Balakin KV,
    3. Hoffman RM,
    4. Pokrovsky VS
    : The potential of methioninase for cancer treatment. Biochim Biophys Acta Rev Cancer 1879(4): 189122, 2024. DOI: 10.1016/j.bbcan.2024.189122
    OpenUrlCrossRef
  16. ↵
    1. Morinaga S,
    2. Han Q,
    3. Kubota Y,
    4. Mizuta K,
    5. Kang BM,
    6. Sato M,
    7. Bouvet M,
    8. Yamamoto N,
    9. Hayashi K,
    10. Kimura H,
    11. Miwa S,
    12. Igarashi K,
    13. Higuchi T,
    14. Tsuchiya H,
    15. Hoffman RM
    : Extensive synergy between recombinant methioninase and eribulin against fibrosarcoma cells but not normal fibroblasts. Anticancer Res 44(3): 921-928, 2024. DOI: 10.21873/anticanres.16886
    OpenUrlAbstract/FREE Full Text
    1. Asano Y,
    2. Han Q,
    3. Li S,
    4. Mizuta K,
    5. Kang BM,
    6. Kim JS,
    7. Miyashi Y,
    8. Yamamoto N,
    9. Hayashi K,
    10. Kimura H,
    11. Miwa S,
    12. Igarashi K,
    13. Higuchi T,
    14. Morinaga S,
    15. Tsuchiya H,
    16. Demura S,
    17. Hoffman RM
    : The combination of the autophagy inhibitor chloroquine and recombinant methioninase has selective synergistic efficacy on human colon cancer cells but not on normal human fibroblasts. Anticancer Res 45(7): 2825-2831, 2025. DOI: 10.21873/anticanres.17651
    OpenUrlAbstract/FREE Full Text
    1. Asano Y,
    2. Han Q,
    3. Mizuta K,
    4. Kang BM,
    5. Kim JS,
    6. Yamamoto N,
    7. Hayashi K,
    8. Kimura H,
    9. Miwa S,
    10. Igarashi K,
    11. Higuchi T,
    12. Morinaga S,
    13. Tsuchiya H,
    14. Demura S,
    15. Hoffman RM
    : Recombinant methioninase and cisplatinum act synergistically to inhibit Lewis lung carcinoma cells but not normal fibroblasts. Anticancer Res 45(5): 1871-1876, 2025. DOI: 10.21873/anticanres.17566
    OpenUrlAbstract/FREE Full Text
    1. Kim J,
    2. Han Q,
    3. Li S,
    4. Kang BM,
    5. Mizuta K,
    6. Asano Y,
    7. Miyashi Y,
    8. Bouvet M,
    9. Hoffman RM
    : The combination of recombinant methioninase and low-dose chloroquine selectively eradicates colon-cancer cells without apparent toxicity on co-cultured normal fibroblasts. Anticancer Res 45(12): 5313-5320, 2025. DOI: 10.21873/anticanres.17870
    OpenUrlAbstract/FREE Full Text
    1. Kim J,
    2. Han Q,
    3. Li S,
    4. Kang BM,
    5. Mizuta K,
    6. Asano Y,
    7. Miyashi Y,
    8. Bouvet M,
    9. Hoffman RM
    : Simultaneous targeting of multiple hallmarks of cancer with recombinant methioninase, rapamycin and chloroquine is specific and synergistic to MiaPaCa-2 pancreatic-cancer cells in contrast to Hs-27 normal fibroblasts. Anticancer Res 45(11): 4765-4770, 2025. DOI: 10.21873/anticanres.17825
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Kim J,
    2. Han Q,
    3. Li S,
    4. Kang BM,
    5. Mizuta K,
    6. Asano Y,
    7. Miyashi Y,
    8. Zhao M,
    9. Bouvet M,
    10. Hoffman RM
    : Combinations of Salmonella typhimurium A1-R, recombinant methioninase, and chloroquine, each targeting fundamental cancer hallmarks, are selectively effective on colon cancer cells compared to normal fibroblasts. Anticancer Res 45(9): 3661-3668, 2025. DOI: 10.21873/anticanres.17729
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Eriksson S,
    2. Prigge JR,
    3. Talago EA,
    4. Arnér ES,
    5. Schmidt EE
    : Dietary methionine can sustain cytosolic redox homeostasis in the mouse liver. Nat Commun 6: 6479, 2015. DOI: 10.1038/ncomms7479
    OpenUrlCrossRefPubMed
  23. ↵
    1. Cho IJ,
    2. Kim D,
    3. Kim EO,
    4. Jegal KH,
    5. Kim JK,
    6. Park SM,
    7. Zhao R,
    8. Ki SH,
    9. Kim SC,
    10. Ku SK
    : Cystine and methionine deficiency promotes ferroptosis by inducing B-cell translocation gene 1. Antioxidants (Basel) 10(10): 1543, 2021. DOI: 10.3390/antiox10101543
    OpenUrlCrossRefPubMed
  24. ↵
    1. Upadhyayula PS,
    2. Higgins DM,
    3. Mela A,
    4. Banu M,
    5. Dovas A,
    6. Zandkarimi F,
    7. Patel P,
    8. Mahajan A,
    9. Humala N,
    10. Nguyen TTT,
    11. Chaudhary KR,
    12. Liao L,
    13. Argenziano M,
    14. Sudhakar T,
    15. Sperring CP,
    16. Shapiro BL,
    17. Ahmed ER,
    18. Kinslow C,
    19. Ye LF,
    20. Siegelin MD,
    21. Cheng S,
    22. Soni R,
    23. Bruce JN,
    24. Stockwell BR,
    25. Canoll P
    : Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism. Nat Commun 14(1): 1187, 2023. DOI: 10.1038/s41467-023-36630-w
    OpenUrlCrossRefPubMed
    1. Badgley MA,
    2. Kremer DM,
    3. Maurer HC,
    4. DelGiorno KE,
    5. Lee HJ,
    6. Purohit V,
    7. Sagalovskiy IR,
    8. Ma A,
    9. Kapilian J,
    10. Firl CEM,
    11. Decker AR,
    12. Sastra SA,
    13. Palermo CF,
    14. Andrade LR,
    15. Sajjakulnukit P,
    16. Zhang L,
    17. Tolstyka ZP,
    18. Hirschhorn T,
    19. Lamb C,
    20. Liu T,
    21. Gu W,
    22. Seeley ES,
    23. Stone E,
    24. Georgiou G,
    25. Manor U,
    26. Iuga A,
    27. Wahl GM,
    28. Stockwell BR,
    29. Lyssiotis CA,
    30. Olive KP
    : Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science 368(6486): 85-89, 2020. DOI: 10.1126/science.aaw9872
    OpenUrlAbstract/FREE Full Text
    1. Dixon SJ,
    2. Patel DN,
    3. Welsch M,
    4. Skouta R,
    5. Lee ED,
    6. Hayano M,
    7. Thomas AG,
    8. Gleason CE,
    9. Tatonetti NP,
    10. Slusher BS,
    11. Stockwell B
    : Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife 3: e02523, 2014. DOI: 10.7554/eLife.02523
    OpenUrlCrossRefPubMed
  27. ↵
    1. Poltorack CD,
    2. Dixon SJ
    : Understanding the role of cysteine in ferroptosis: progress & paradoxes. FEBS J 289(2): 374-385, 2022. DOI: 10.1111/febs.15842. Epub 2021 Apr 7.
    OpenUrlCrossRef
  28. ↵
    1. Miyashi Y,
    2. Mizuta K,
    3. Asano Y,
    4. Kang BM,
    5. Kim JS,
    6. Han Q,
    7. Li S,
    8. Bouvet M,
    9. Tome Y,
    10. Nishida K,
    11. Hoffman RM
    : Methionine restriction, not cysteine restriction, is a cancer-specific vulnerability. Anticancer Res 46(1): 135-141, 2026. DOI: 10.21873/anticanres.17929
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. Asano Y,
    2. Han Q,
    3. Li S,
    4. Mizuta K,
    5. Kang BM,
    6. Kim JS,
    7. Miyashi Y,
    8. Yamamoto N,
    9. Hayashi K,
    10. Kimura H,
    11. Miwa S,
    12. Igarashi K,
    13. Higuchi T,
    14. Morinaga S,
    15. Tsuchiya H,
    16. Demura S,
    17. Hoffman RM
    : Very rapid eradication of a large squamous-cell carcinoma of the head and neck treated with first-line combination chemotherapy, a low-methionine diet, and oral recombinant methioninase. Anticancer Res 45(11): 5225-5231, 2025. DOI: 10.21873/anticanres.17862
    OpenUrlAbstract/FREE Full Text
  30. ↵
    1. Asano Y,
    2. Han Q,
    3. Li S,
    4. Sato T,
    5. Hozumi C,
    6. Kang BM,
    7. Kim JS,
    8. Miyashi Y,
    9. Yamamoto N,
    10. Hayashi K,
    11. Kimura H,
    12. Miwa S,
    13. Igarashi K,
    14. Higuchi T,
    15. Morinaga S,
    16. Tsuchiya H,
    17. Demura S,
    18. Hoffman RM
    : Rapid eradication of extensive spinal metastases in a prostate-cancer patient taking androgen-deprivation therapy, chemotherapy, and oral recombinant methioninase on a low-methionine diet. Anticancer Res 45(12): 5799-5805, 2025. DOI: 10.21873/anticanres.17912
    OpenUrlAbstract/FREE Full Text
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Sulfasalazine an Inhibitor of System xC− (Cystine/glutamate Antiporter), Combined With Recombinant Methioninase, Inhibits Both Cancer and Normal Cells, Suggesting Lack of Cancer Selectivity of Cysteine Restriction
JINSOO KIM, QINGHONG HAN, SHUKUAN LI, BYUNG MO KANG, YUTA MIYASHI, TOMOYUKI ISHIGURO, MICHAEL BOUVET, ROBERT M. HOFFMAN
Anticancer Research May 2026, 46 (5) 2353-2359; DOI: 10.21873/anticanres.18122
Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords