Research ArticleExperimental Studies
Open Access

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

YOHEI ASANO, QINGHONG HAN, SHUKUAN LI, KOHEI MIZUTA, BYUNG MO KANG, JIN SOO KIM, YUTA MIYASHI, NORIO YAMAMOTO, KATSUHIRO HAYASHI, HIROAKI KIMURA, SHINJI MIWA, KENTARO IGARASHI, TAKASHI HIGUCHI, SEI MORINAGA, HIROYUKI TSUCHIYA, SATORU DEMURA and ROBERT M. HOFFMAN
Anticancer Research July 2025, 45 (7) 2825-2831; DOI: https://doi.org/10.21873/anticanres.17651

Abstract

Background/Aim: Metastatic colon cancer is a recalcitrant disease with a 5-year survival rate of 15.7-26.0%, and more effective treatments are necessary. Methionine addiction is a fundamental and general hallmark of cancer. Targeting methionine addiction with recombinant methioninase (rMETase) is effective against colon-cancer cells. Combining the autophagy inhibitor chloroquine with rMETase has shown efficacy on breast cancer and osteosarcoma cells. The present study aimed to determine whether the combination of chloroquine and rMETase is selectively synergistic against colon-cancer cells in contrast to normal fibroblasts.

Materials and Methods: The present study used the human colon-cancer cell line HCT-116 and Hs27 normal human fibroblasts. Cells (1×103) were seeded in each well of 96-well plates and cultured in Dulbecco’s modified Eagle’s medium (DMEM) with 10% fetal bovine serum at 37°C in 5% CO2 for 24 h. Cells were then treated with rMETase at concentrations ranging from 0.0625 U/ml to 8 U/ml or chloroquine at concentrations ranging from 0.5 μM to 128 μM for 72 h. Drug-sensitivity curves were generated using a cell viability assay with the WST-8 reagent. The half-maximal inhibitory concentration (IC50) of rMETase and chloroquine against HCT-116 and Hs27 cells was calculated. Cell viability of cells treated with rMETase alone, chloroquine alone, and the combination of rMETase and chloroquine at IC50 concentrations was assessed.

Results: The IC50 concentrations of rMETase on HCT-116 and Hs27 were 0.61 μM and 0.67 μM, respectively. The IC50 concentrations of chloroquine on HCT-116 and Hs27 were 7.52 U/ml and 10.85 U/ml, respectively. Cell viability assays using these IC50 concentrations showed that the combination of rMETase and chloroquine had synergistic efficacy on HCT-116 cells, but not on Hs27 cells.

Conclusion: The combination of chloroquine and rMETase had synergistic efficacy on colon-cancer cells, but not on normal fibroblasts. rMETase is used clinically as an oral supplement, and chloroquine is a drug approved for clinical use. Therefore, the combination of rMETase and chloroquine has the potential for safe clinical application.

Keywords:

Introduction

Colon cancer is the second leading cause of cancer-related deaths according to recent reports (1), and approximately 25% of colon-cancer cases are diagnosed at a metastatic stage (2). Metastatic colon cancer is a recalcitrant disease with a 5-year survival rate of 15.7-26.0% (3). The treatment of metastatic colon cancer remains a formidable challenge, highlighting the urgent need for novel therapeutic strategies that can overcome the limitations of current treatment regimens and improve clinical efficacy.

Methionine addiction, known as the Hoffman effect, is a fundamental and general hallmark of cancer (4-15) and targeting methionine addiction with recombinant methioninase (rMETase) is effective against colon-cancer cells (16).

Chloroquine (CQ), a widely used antimalarial and immunomodulatory drug, also has anticancer efficacy. CQ has been repurposed in cancer therapy due to its ability to modulate autophagy, alter the tumor microenvironment, and enhance the efficacy of conventional cancer therapies (17-18). Our previous studies have shown that combining CQ with rMETase has synergistic efficacy on breast-cancer and osteosarcoma cells (19, 20).

The present study aimed to determine the efficacy of the combination of rMETase and CQ against colon-cancer cells compared to normal fibroblasts.

Materials and Methods

Cell culture. The human colon-cancer cell line (HCT-116) and normal fibroblasts (Hs27) were obtained from the American Type Culture Collection (Manassas, VA, USA). The cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin at 37°C in a humidified incubator containing 5% CO2.

Drugs and cell viability assay. rMETase was produced at AntiCancer Inc. (San Diego, CA, USA) by fermentation of recombinant Escherichia coli transformed with the Pseudomonas putida methioninase gene as previously (21). Chloroquine diphosphate was obtained from Sigma-Aldrich (St. Louis, MO, USA).

Cells were seeded at a density of 1×103 cells per well in 100 μl of DMEM in 96-well plates and incubated for 24 h. Following confirmation of cell adherence and proliferation, cells were treated with rMETase at concentrations ranging from 0.0625 U/ml to 8 U/ml or CQ at concentrations ranging from 0.5 μM to 128 μM for 72 h. Thereafter, the WST-8 reagent (10 μl) (Dojindo Laboratories, Kumamoto, Japan) was added to each well, followed by incubation for 1 hour. Absorbance at 450 nm was measured using a microplate reader (Sunrise, Tecan, Männedorf, Switzerland).

To determine the half-maximal inhibitory concentration (IC50) of rMETase and CQ on HCT-116 and Hs27 cells, drug-sensitivity curves were generated using Microsoft Excel for Mac 2024 (ver. 16.89.1; Microsoft, Redmond, WA, USA), ImageJ (ver. 1.54g; National Institutes of Health, Bethesda, MD, USA), and GraphPad Prism (ver. 10.4.1; GraphPad Software, Inc., San Diego, CA, USA). The IC50 values were calculated accordingly.

Efficacy of the combination of rMETase and CQ on HCT-116 and Hs27 cells. Cells were seeded in 96-well plates with the same procedure as described above. To evaluate the viability of cells treated with each drug and their combination, the cells were divided into the following four groups: 1) control (DMEM), 2) rMETase alone (at IC50), 3) CQ alone (at IC50), and 4) combination of rMETase and CQ (at each IC50). After 72 h of treatment, absorbance was measured at 450 nm using the same procedure as described above, and the relative cell viability in each treatment group was calculated.

Statistical analysis. All experiments were performed in triplicate and independently repeated twice. All data are expressed as the mean±standard deviation and statistical comparisons among treatment groups were performed using one-way analysis of variance (ANOVA), followed by Tukey’s post hoc test for multiple comparisons. All statistical analyses were performed using EZR software (Saitama Medical Center, Jichi Medical University, Saitama, Japan). A p-value of ≤0.05 was considered to indicate statistical significance.

Results

Determination of the IC50 of rMETase and CQ on HCT-116 colon-cancer and Hs27 normal fibroblasts. Drug sensitivity curves of rMEase and CQ on HCT-116 and Hs27 were generated based on a cell viability assay (Figure 1 and Figure 2). The IC50 of rMETase alone and CQ alone on HCT-116 were 0.61 U/ml and 7.52 μM, respectively (Figure 1). The IC50 of rMETase alone and CQ alone on Hs27 were 0.67 U/ml and 10.85 μM, respectively (Figure 2).

Figure 1.
Figure 1.

Drug-sensitivity curves of CQ and recombinant rMETase for HCT-116 colon-cancer cells. CQ: Chloroquine; rMETase: recombinant methioninase. Please see Materials and Methods for details.

Figure 2.
Figure 2.

Drug-sensitivity curves of CQ and rMETase on Hs27 normal fibroblasts. CQ: Chloroquine; rMETase: recombinant methioninase. Please see Materials and Methods for details.

Synergy of the combination of rMETase and CQ on HCT-116 colon-cancer cells and Hs27 normal fibroblasts. Cells were treated with each drug and their combination at the IC50 concentrations and cell viability was assessed. The combination of rMETase and CQ on HCT-116 showed significantly lower cell viability than either drug alone (both p<0.05, Figure 3A). In contrast, the combination of rMETase and CQ for Hs27 showed similar cell viability as monotherapy with each drug (Figure 3B).

Figure 3.
Figure 3.

(A) Relative cell viability of HCT-116 cells and (B) Hs27 fibroblasts treated with rMETase, CQ, and the combination of rMETase and CQ using each half-maximal inhibitory concentration (IC50). *p<0.05. CQ: Chloroquine; rMETase: recombinant methioninase. Please see Materials and Methods for details.

Discussion

The present study showed that the combination of CQ with rMETase had selective synergy on colon-cancer cells (HCT-116), but not on normal cells (Hs27). Recent studies have explored various anti-cancer mechanisms of CQ, including the induction of cell-cycle arrest in the G1 phase via autophagy inhibition and the promotion of apoptosis in cancer cells through activation of the caspase cascade (17, 18, 22, 23). Additionally, CQ enhances the efficacy of chemotherapy by normalizing the structure and function of tumor vasculature, as well as by suppressing tumor invasion and metastasis. The anti-tumor efficacy of CQ has been demonstrated in several malignancies, including primary effusion lymphoma, lung cancer, pancreatic cancer, colorectal cancer, breast cancer and osteosarcoma (17, 18, 22-24).

In the present study, we focused on the combination of rMETase and CQ as a novel therapeutic strategy for colon cancer, a leading cause of cancer-related mortality worldwide for which improved treatment outcomes are urgently needed (1). rMETase, which was developed as an oral agent for methionine restriction, targets the methionine addiction of cancer cells and selectively induces cell-cycle arrest in the S/G2 phase, which may be the basis of the synergy in combination with various anticancer agents against colon and other cancers (14, 25, 26). The combination of rMETase and CQ may enhance therapeutic efficacy by capturing cancer cells that escape from cell-cycle arrest induced by either drug alone, thereby contributing to their synergistic interaction. The anticancer activity of CQ in colon cancer has been linked to its interaction with palmitoyl-protein thioesterase 1 (PPT1), a lysosomal protein abundantly expressed in various cancer cells (27). However, the mechanisms beyond this interaction remain poorly understood. For the clinical application of CQ, further research is needed to clarify the mechanisms of its various anticancer effects.

Study limitations. The study design was only in vitro, and it focused on the inhibitory efficacy of rMETase and CQ on cell viability, leaving the mechanisms to be determine. Further studies on autophagy and apoptosis are planned to elucidate the mechanism of the combination of rMETase and CQ.

Conclusion

The combination of rMETase and CQ has selective synergy on colon-cancer cells but not on normal fibroblasts. In vivo studies are needed to follow the present study to demonstrate efficacy against colon cancer in mouse models, particularly the patient-derived orthotopic xenograft (PDOX) models, as well as in the clinic (28-30).

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, John W. Littlefield, MD, Professor Li Jiaxi, Masaki Kitajima, MD, Joseph R. Bertino, MD, Shigeo Yagi, PhD, J.A.R Mead, PhD, Eugene P. Frenkel, MD, Professor Lev Bergelson, Professor Sheldon Penman, Professor John R. Raper, and Joseph Leighton, MD. The Robert M. Hoffman Foundation for Cancer Research provided funds for the present study.

Footnotes

  • Authors’ Contributions

    YA and RMH designed the study. QH and SL provided rMETase. YA performed experiments and formal analysis. YA was the major contributor to writing – original draft and RMH revised the manuscript. QH, SL, KM, BMK, JSK, YM, NY, KH, HK, ShM, KI, TH, SeM, HT, and SD critically read and approved the final manuscript.

  • Conflicts of Interest

    The Authors have no conflicts of interest.

  • 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 June 3, 2025.
  • Revision received June 9, 2025.
  • Accepted June 10, 2025.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

References

  1. ↵
    1. Bray F,
    2. Laversanne M,
    3. Sung H,
    4. Ferlay J,
    5. Siegel RL,
    6. Soerjomataram I,
    7. Jemal A
    : Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 74(3): 229-263, 2024. DOI: 10.3322/caac.21834
    OpenUrlCrossRef
  2. ↵
    1. Fan A,
    2. Wang B,
    3. Wang X,
    4. Nie Y,
    5. Fan D,
    6. Zhao X,
    7. Lu Y
    : Immunotherapy in colorectal cancer: current achievements and future perspective. Int J Biol Sci 17(14): 3837-3849, 2021. DOI: 10.7150/ijbs.64077
    OpenUrlCrossRefPubMed
  3. ↵
    1. Zeineddine FA,
    2. Zeineddine MA,
    3. Yousef A,
    4. Gu Y,
    5. Chowdhury S,
    6. Dasari A,
    7. Huey RW,
    8. Johnson B,
    9. Kee B,
    10. Lee MS,
    11. Morelli MP,
    12. Morris VK,
    13. Overman MJ,
    14. Parseghian C,
    15. Raghav K,
    16. Willis J,
    17. Wolff RA,
    18. Kawaguchi Y,
    19. Vauthey JN,
    20. Sun R,
    21. Kopetz S,
    22. Shen JP
    : Survival improvement for patients with metastatic colorectal cancer over twenty years. NPJ Precis Oncol 7(1): 16, 2023. DOI: 10.1038/s41698-023-00353-4
    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 USA 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 USA 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. 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. Inubushi S,
    3. Han Q,
    4. Tashiro Y,
    5. Sugisawa N,
    6. Hamada K,
    7. Aoki Y,
    8. Miyake K,
    9. Matsuyama R,
    10. Bouvet M,
    11. Clarke SG,
    12. Endo I,
    13. Hoffman RM
    : Linkage of methionine addiction, histone lysine hypermethylation, and malignancy. iScience 25(4): 104162, 2022. DOI: 10.1016/j.isci.2022.104162
    OpenUrlCrossRefPubMed
    1. Aoki Y,
    2. Han Q,
    3. Tome Y,
    4. Yamamoto J,
    5. Kubota Y,
    6. Masaki N,
    7. Obara K,
    8. Hamada K,
    9. Wang JD,
    10. Inubushi S,
    11. Bouvet M,
    12. Clarke SG,
    13. Nishida K,
    14. Hoffman RM
    : Reversion of methionine addiction of osteosarcoma cells to methionine independence results in loss of malignancy, modulation of the epithelial-mesenchymal phenotype and alteration of histone-H3 lysine-methylation. Front Oncol 12: 1009548, 2022. DOI: 10.3389/fonc.2022.1009548
    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. Wang Z,
    2. Yip LY,
    3. Lee JHJ,
    4. Wu Z,
    5. Chew HY,
    6. Chong PKW,
    7. Teo CC,
    8. Ang HY,
    9. Peh KLE,
    10. Yuan J,
    11. Ma S,
    12. Choo LSK,
    13. Basri N,
    14. Jiang X,
    15. Yu Q,
    16. Hillmer AM,
    17. Lim WT,
    18. Lim TKH,
    19. Takano A,
    20. Tan EH,
    21. Tan DSW,
    22. Ho YS,
    23. Lim B,
    24. Tam WL
    : Methionine is a metabolic dependency of tumor-initiating cells. Nat Med 25(5): 825-837, 2019. DOI: 10.1038/s41591-019-0423-5
    OpenUrlCrossRefPubMed
    1. Lin DW,
    2. Carranza FG,
    3. Borrego S,
    4. Lauinger L,
    5. Dantas de Paula L,
    6. Pulipelli HR,
    7. Andronicos A,
    8. Hertel KJ,
    9. Kaiser P
    : Nutrient control of splice site selection contributes to methionine addiction of cancer. Mol Metab 93: 102103, 2025. DOI: 10.1016/j.molmet.2025.102103
    OpenUrlCrossRefPubMed
    1. Stern PH,
    2. Hoffman RM
    : Enhanced in vitro selective toxicity of chemotherapeutic agents for human cancer cells based on a metabolic defect. J Natl Cancer Inst 76(4): 629-639, 1986. DOI: 10.1093/jnci/76.4.629
    OpenUrlCrossRefPubMed
  14. ↵
    1. Hoffman RM,
    2. Jacobsen SJ
    : Reversible growth arrest in simian virus 40-transformed human fibroblasts. Proc Natl Acad Sci USA 77(12): 7306-7310, 1980. DOI: 10.1073/pnas.77.12.7306
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Tisdale MJ
    : Effect of methionine deprivation on methylation and synthesis of macromolecules. Br J Cancer 42(1): 121-128, 1980. DOI: 10.1038/bjc.1980.210
    OpenUrlCrossRefPubMed
  16. ↵
    1. Kim MJ,
    2. Han Q,
    3. Bouvet M,
    4. Hoffman RM,
    5. Park JH
    : Recombinant oral methioninase (o-rMETase) combined with oxaliplatinum plus 5-fluorouracil improves survival of mice with massive colon-cancer peritoneal carcinomatosis. Anticancer Res 43(1): 19-24, 2023. DOI: 10.21873/anticanres.16129
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Levy JMM,
    2. Towers CG,
    3. Thorburn A
    : Targeting autophagy in cancer. Nat Rev Cancer 17(9): 528-542, 2017. DOI: 10.1038/nrc.2017.53
    OpenUrlCrossRefPubMed
  18. ↵
    1. Maes H,
    2. Kuchnio A,
    3. Peric A,
    4. Moens S,
    5. Nys K,
    6. De Bock K,
    7. Quaegebeur A,
    8. Schoors S,
    9. Georgiadou M,
    10. Wouters J,
    11. Vinckier S,
    12. Vankelecom H,
    13. Garmyn M,
    14. Vion AC,
    15. Radtke F,
    16. Boulanger C,
    17. Gerhardt H,
    18. Dejana E,
    19. Dewerchin M,
    20. Ghesquière B,
    21. Annaert W,
    22. Agostinis P,
    23. Carmeliet P
    : Tumor vessel normalization by chloroquine independent of autophagy. Cancer Cell 26(2): 190-206, 2014. DOI: 10.1016/j.ccr.2014.06.025
    OpenUrlCrossRefPubMed
  19. ↵
    1. Morinaga S,
    2. Han Q,
    3. Mizuta K,
    4. Kang BM,
    5. Bouvet M,
    6. Yamamoto N,
    7. Hayashi K,
    8. Kimura H,
    9. Miwa S,
    10. Igarashi K,
    11. Higuchi T,
    12. Tsuchiya H,
    13. Demura S,
    14. Hoffman RM
    : Highly synergistic eradication of 143B osteosarcoma cells in vitro by the combination of recombinant methioninase, chloroquine, and rapamycin targeting methionine addiction, autophagy, and mTOR, respectively. Anticancer Res 45(3): 935-941, 2025. DOI: 10.21873/anticanres.17481
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Kim J,
    2. Han Q,
    3. Kang BM,
    4. Mizuta K,
    5. Asano Y,
    6. Bouvet M,
    7. Hoffman RM
    : Combination of recombinant methioninase with rapamycin or chloroquine is synergistic to highly inhibit triple-negative breast cancer cells in vitro. Anticancer Res 45(5): 1853-1859, 2025. DOI: 10.21873/anticanres.17564
    OpenUrlAbstract/FREE Full Text
  21. ↵
    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
  22. ↵
    1. Sasaki K,
    2. Tsuno NH,
    3. Sunami E,
    4. Tsurita G,
    5. Kawai K,
    6. Okaji Y,
    7. Nishikawa T,
    8. Shuno Y,
    9. Hongo K,
    10. Hiyoshi M,
    11. Kaneko M,
    12. Kitayama J,
    13. Takahashi K,
    14. Nagawa H
    : Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells. BMC Cancer 10: 370, 2010. DOI: 10.1186/1471-2407-10-370
    OpenUrlCrossRefPubMed
  23. ↵
    1. Choi JH,
    2. Yoon JS,
    3. Won YW,
    4. Park BB,
    5. Lee YY
    : Chloroquine enhances the chemotherapeutic activity of 5-fluorouracil in a colon cancer cell line via cell cycle alteration. APMIS 120(7): 597-604, 2012. DOI: 10.1111/j.1600-0463.2012.02876.x
    OpenUrlCrossRefPubMed
  24. ↵
    1. Liu Y,
    2. Zhu Y,
    3. Gu L,
    4. Li K,
    5. Ma A,
    6. Liu L,
    7. Meng Y,
    8. Zhang J,
    9. Shen S,
    10. Shi Q,
    11. Liu D,
    12. Zhang X,
    13. Zhang S,
    14. Chai X,
    15. Gao P,
    16. Xing J,
    17. Wang Y,
    18. Chen H,
    19. Liu R,
    20. Du Q,
    21. Liu H,
    22. Dai L,
    23. Wang J
    : Chloroquine suppresses colorectal cancer progression via targeting CHKA and PFKM to inhibit the PI3K/AKT pathway and the Warburg effect. Int J Biol Sci 21(4): 1619-1631, 2025. DOI: 10.7150/ijbs.101921
    OpenUrlCrossRefPubMed
  25. ↵
    1. Yano S,
    2. Li S,
    3. Han Q,
    4. Tan Y,
    5. Bouvet M,
    6. Fujiwara T,
    7. Hoffman RM
    : Selective methioninase-induced trap of cancer cells in S/G2 phase visualized by FUCCI imaging confers chemosensitivity. Oncotarget 5(18): 8729-8736, 2014. DOI: 10.18632/oncotarget.2369
    OpenUrlCrossRefPubMed
  26. ↵
    1. Kubota Y,
    2. Han Q,
    3. Aoki Y,
    4. Masaki N,
    5. Obara K,
    6. Hamada K,
    7. Hozumi C,
    8. Wong ACW,
    9. Bouvet M,
    10. Tsunoda T,
    11. Hoffman RM
    : Synergy of combining methionine restriction and chemotherapy: the disruptive next generation of cancer treatment. Cancer Diagn Progn 3(3): 272-281, 2023. DOI: 10.21873/cdp.10212
    OpenUrlCrossRefPubMed
  27. ↵
    1. Rebecca VW,
    2. Nicastri MC,
    3. Fennelly C,
    4. Chude CI,
    5. Barber-Rotenberg JS,
    6. Ronghe A,
    7. McAfee Q,
    8. McLaughlin NP,
    9. Zhang G,
    10. Goldman AR,
    11. Ojha R,
    12. Piao S,
    13. Noguera-Ortega E,
    14. Martorella A,
    15. Alicea GM,
    16. Lee JJ,
    17. Schuchter LM,
    18. Xu X,
    19. Herlyn M,
    20. Marmorstein R,
    21. Gimotty PA,
    22. Speicher DW,
    23. Winkler JD,
    24. Amaravadi RK
    : PPT1 promotes tumor growth and is the molecular target of chloroquine derivatives in cancer. Cancer Discov 9(2): 220-229, 2019. DOI: 10.1158/2159-8290.CD-18-0706
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Han Q,
    2. Tan Y,
    3. Hoffman RM
    : Oral dosing of recombinant methioninase is associated with a 70% drop in PSA in a patient with bone-metastatic prostate cancer and 50% reduction in circulating methionine in a high-stage ovarian cancer patient. Anticancer Res 40(5): 2813-2819, 2020. DOI: 10.21873/anticanres.14254
    OpenUrlAbstract/FREE Full Text
    1. Kubota Y,
    2. Han Q,
    3. Masaki N,
    4. Hozumi C,
    5. Hamada K,
    6. Aoki Y,
    7. Obara K,
    8. Tsunoda T,
    9. Hoffman RM
    : Elimination of axillary-lymph-node metastases in a patient with invasive lobular breast cancer treated by first-line neo-adjuvant chemotherapy combined with methionine restriction. Anticancer Res 42(12): 5819-5823, 2022. DOI: 10.21873/anticanres.16089
    OpenUrlAbstract/FREE Full Text
  30. ↵
    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
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
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
YOHEI ASANO, QINGHONG HAN, SHUKUAN LI, KOHEI MIZUTA, BYUNG MO KANG, JIN SOO KIM, YUTA MIYASHI, NORIO YAMAMOTO, KATSUHIRO HAYASHI, HIROAKI KIMURA, SHINJI MIWA, KENTARO IGARASHI, TAKASHI HIGUCHI, SEI MORINAGA, HIROYUKI TSUCHIYA, SATORU DEMURA, ROBERT M. HOFFMAN
Anticancer Research Jul 2025, 45 (7) 2825-2831; DOI: 10.21873/anticanres.17651
Twitter logo Facebook logo Mendeley logo

Jump to section

Related Articles

Cited By...

More in this TOC Section

Keywords