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Recent Patents on Anti-Cancer Drug Discovery

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ISSN (Print): 1574-8928
ISSN (Online): 2212-3970

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General Research Article

Gliotoxin Induced Ferroptosis by Downregulating SUV39H1 Expression in Esophageal Cancer Cells

Author(s): Shengqiang Zhang, Jida Guo, Hongyan Zhang, Lu Tong and Linyou Zhang*

Volume 18, Issue 3, 2023

Published on: 27 September, 2022

Page: [397 - 407] Pages: 11

DOI: 10.2174/1574892817666220905114120

Price: $65

Abstract

Background: Gliotoxin, a secondary metabolite isolated from marine-derived Aspergillus fumigatus, has demonstrated anti-tumor properties in several cancers. Ferroptosis, a recently discovered type of programmed cell death that depends on the accumulation of iron and lipid peroxides, participates in the occurrence and development of various diseases, including cancer. A recent patent, US20200383943, has suggested that the promotion of ferroptosis is a method of cancer treatment. Therefore, the development of drugs that induce ferroptosis in cancer cells would constitute a novel therapeutic approach.

Objective: Gliotoxin is a natural compound which has exhibited anti-tumor properties in multiple cancers, however, studies of the effect of gliotoxin on esophageal cancer are lacking. Although cancer treatment has shown great progress, including traditional surgery, chemotherapy, radiotherapy, and immunotherapy, the prognosis of esophageal cancer is still poor. Therefore, the development of new treatment approaches for esophageal cancer is necessary.

Methods: The effects of gliotoxin on esophageal cancer cells were determined by functional assays, such as CCK-8, wound healing and transwell assays. We used online tools to predict the target genes of gliotoxin, followed by further verification using Western blotting assays. To assess the role of gliotxin in inducing ferroptosis in esophageal cancer, we detected characteristics associated with ferroptosis including ROS, MDA, GSH and Fe2+.

Results: Using online tools SEA and SwissTargetPrediction, we predicted that SUV39H1 was the gliotoxin target gene. Furthermore, in esophageal cancer tissues, SUV39H1 was expressed at higher levels than in normal tissues, while in patients with Esophageal Squamous Cell Carcinoma (ESCC), high expression levels of SUV39H1 indicated a poor prognosis. In vitro, we observed that gliotoxin increased ESCC cell death and inhibited cell migration. We treated ESCC cells with pan-caspase inhibitor Z-VAD-FMK or ferroptosis inhibitors, including Fer-1 and DFO. Our results showed that Fer-1 and DFO reduced the toxic effects of gliotoxin, while Z-VAD-FMK did not. Furthermore, gliotoxin treatment reduced tumor weight and volume in the xenograft tumor mouse model.

Conclusion: In summary, our findings indicate that gliotoxin downregulated SUV39H1 expression in ESCC cells and induced ferroptosis, suggesting a novel natural therapy for ESSC.

Keywords: Gliotoxin, natural compounds, esophageal squamous cell carcinoma, ferroptosis, SUV39H1, cancer therapy.

« Previous Next »
[1]
Sung H, Ferlay J, Siegel RL. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71(3): 209-49.
[http://dx.doi.org/10.3322/caac.21660 ] [PMID: 33538338]
[2]
Chen YH, Lu HI, Lo CM, Hsiao CC, Li SH. NOX4 overexpression is a poor prognostic factor in patients undergoing curative esophagec-tomy for esophageal squamous cell carcinoma. Surgery 2020; 167(3): 620-7.
[http://dx.doi.org/10.1016/j.surg.2019.11.017 ] [PMID: 31889545]
[3]
Lin T. Novel use of adapalene in treating esophageal cancer and gastrointestinal stromal tumor. US Patent 20160113895, 2016.
[4]
Prieur A. Compositions and methods for detecting and treating esophageal cancer. US Patent 20190011447, 2019.
[5]
Li X, Zhang L, Guo X. et al. Self-assembled RNA nanocarrier-mediated chemotherapy combined with molecular targeting in the treatment of esophageal squamous cell carcinoma. J Nanobiotechnology 2021; 19(1): 388.
[http://dx.doi.org/10.1186/s12951-021-01135-5 ] [PMID: 34823537]
[6]
Gaschler MM, Andia AA, Liu H. et al. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol 2018; 14(5): 507-15.
[http://dx.doi.org/10.1038/s41589-018-0031-6 ] [PMID: 29610484]
[7]
Hou W, Xie Y, Song X. et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 2016; 12(8): 1425-8.
[http://dx.doi.org/10.1080/15548627.2016.1187366 ] [PMID: 27245739]
[8]
Zou Y, Palte MJ, Deik AA. et al. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferrop-tosis. Nat Commun 2019; 10(1): 1617.
[http://dx.doi.org/10.1038/s41467-019-09277-9 ] [PMID: 30962421]
[9]
Liang C, Zhang X, Yang M, Dong X. Recent progress in ferroptosis inducers for cancer therapy. Adv Mater 2019; 31(51), 1904197.
[http://dx.doi.org/10.1002/adma.201904197 ] [PMID: 31595562]
[10]
Hassannia B, Vandenabeele P, Vanden Berghe T. Targeting ferroptosis to iron out cancer. Cancer Cell 2019; 35(6): 830-49.
[http://dx.doi.org/10.1016/j.ccell.2019.04.002 ] [PMID: 31105042]
[11]
Zhou B, Liu J, Kang R, Klionsky DJ, Kroemer G, Tang D. Ferroptosis is a type of autophagy-dependent cell death. Semin Cancer Biol 2020; 66: 89-100.
[http://dx.doi.org/10.1016/j.semcancer.2019.03.002 ] [PMID: 30880243]
[12]
Wang J, Yin X, He W, Xue W, Zhang J, Huang Y. SUV39H1 deficiency suppresses clear cell renal cell carcinoma growth by inducing fer-roptosis. Acta Pharm Sin B 2021; 11(2): 406-19.
[http://dx.doi.org/10.1016/j.apsb.2020.09.015 ] [PMID: 33643820]
[13]
Liu B, Wang Z, Zhang L, Ghosh S, Zheng H, Zhou Z. Depleting the methyltransferase Suv39h1 improves DNA repair and extends lifespan in a progeria mouse model. Nat Commun 2013; 4(1): 1868.
[http://dx.doi.org/10.1038/ncomms2885 ] [PMID: 23695662]
[14]
Albacker CE, Storer NY, Langdon EM. et al. The histone methyltransferase SUV39H1 suppresses embryonal rhabdomyosarcoma for-mation in zebrafish. PLoS One 2013; 8(5), e64969.
[http://dx.doi.org/10.1371/journal.pone.0064969 ] [PMID: 23705022]
[15]
Lu C, Yang D, Klement JD. et al. SUV39H1 represses the expression of cytotoxic T-lymphocyte effector genes to promote colon tumor immune evasion. Cancer Immunol Res 2019; 7(3): 414-27.
[http://dx.doi.org/10.1158/2326-6066.CIR-18-0126 ] [PMID: 30610059]
[16]
Yang Z, He L, Lin K. et al. The KMT1A-GATA3-STAT3 circuit is a novel self-renewal signaling of human bladder cancer stem cells. Clin Cancer Res 2017; 23(21): 6673-85.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-0882 ] [PMID: 28765327]
[17]
Chiba T, Saito T, Yuki K. et al. Histone lysine methyltransferase SUV39H1 is a potent target for epigenetic therapy of hepatocellular car-cinoma. Int J Cancer 2015; 136(2): 289-98.
[http://dx.doi.org/10.1002/ijc.28985 ] [PMID: 24844570]
[18]
Gardiner DM, Waring P, Howlett BJ. The epipolythiodioxopiperazine (ETP) class of fungal toxins: Distribution, mode of action, functions and biosynthesis. Microbiology (Reading) 2005; 151(4): 1021-32.
[http://dx.doi.org/10.1099/mic.0.27847-0 ] [PMID: 15817772]
[19]
Scharf DH, Brakhage AA, Mukherjee PK. Gliotoxin - bane or boon? Environ Microbiol 2016; 18(4): 1096-109.
[http://dx.doi.org/10.1111/1462-2920.13080 ] [PMID: 26443473]
[20]
Chen J, Wang C, Lan W. et al. Gliotoxin inhibits proliferation and induces apoptosis in colorectal cancer cells. Mar Drugs 2015; 13(10): 6259-73.
[http://dx.doi.org/10.3390/md13106259 ] [PMID: 26445050]
[21]
Vigushin DM, Mirsaidi N, Brooke G. et al. Gliotoxin is a dual inhibitor of farnesyltransferase and geranylgeranyltransferase I with anti-tumor activity against breast cancer in vivo. Med Oncol 2004; 21(1): 21-30.
[http://dx.doi.org/10.1385/MO:21:1:21 ] [PMID: 15034210]
[22]
Hubmann R, Sieghart W. Tumor treatment with gliotoxin derivatives. US Patent 20090029974, 2009.
[23]
Nguyen VT, Lee J, Qian ZJ. et al. Gliotoxin isolated from marine fungus Aspergillus sp. induces apoptosis of human cervical cancer and chondrosarcoma cells. Mar Drugs 2013; 12(1): 69-87.
[http://dx.doi.org/10.3390/md12010069 ] [PMID: 24368570]
[24]
Goldman MJ, Craft B, Hastie M. et al. Visualizing and interpreting cancer genomics data via the Xena platform. Nat Biotechnol 2020; 38(6): 675-8.
[http://dx.doi.org/10.1038/s41587-020-0546-8 ] [PMID: 32444850]
[25]
Chandrashekar DS, Bashel B, Balasubramanya SAH. et al. UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia 2017; 19(8): 649-58.
[http://dx.doi.org/10.1016/j.neo.2017.05.002 ] [PMID: 28732212]
[26]
Keiser MJ, Roth BL, Armbruster BN, Ernsberger P, Irwin JJ, Shoichet BK. Relating protein pharmacology by ligand chemistry. Nat Biotechnol 2007; 25(2): 197-206.
[http://dx.doi.org/10.1038/nbt1284 ] [PMID: 17287757]
[27]
Gfeller D, Michielin O, Zoete V. Shaping the interaction landscape of bioactive molecules. Bioinformatics 2013; 29(23): 3073-9.
[http://dx.doi.org/10.1093/bioinformatics/btt540 ] [PMID: 24048355]
[28]
Daina A, Michielin O, Zoete V. SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res 2019; 47(W1), W357.-64
[http://dx.doi.org/10.1093/nar/gkz382 ] [PMID: 31106366]
[29]
Wang H, Lin D, Yu Q. et al. A promising future of ferroptosis in tumor therapy. Front Cell Dev Biol 2021; 9, 629150.
[http://dx.doi.org/10.3389/fcell.2021.629150 ] [PMID: 34178977]
[30]
Friedmann Angeli JP, Krysko DV, Conrad M. Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion. Nat Rev Cancer 2019; 19(7): 405-14.
[http://dx.doi.org/10.1038/s41568-019-0149-1 ] [PMID: 31101865]
[31]
Xu H, Ye D, Ren M, Zhang H, Bi F. Ferroptosis in the tumor microenvironment: Perspectives for immunotherapy. Trends Mol Med 2021; 27(9): 856-67.
[http://dx.doi.org/10.1016/j.molmed.2021.06.014 ] [PMID: 34312075]
[32]
Xie Y, Hou W, Song X. et al. Ferroptosis: Process and function. Cell Death Differ 2016; 23(3): 369-79.
[http://dx.doi.org/10.1038/cdd.2015.158 ] [PMID: 26794443]
[33]
Chen P, Wu Q, Feng J. et al. Erianin, a novel dibenzyl compound in Dendrobium extract, inhibits lung cancer cell growth and migration via calcium/calmodulin-dependent ferroptosis. Signal Transduct Target Ther 2020; 5(1): 51.
[http://dx.doi.org/10.1038/s41392-020-0149-3 ] [PMID: 32382060]
[34]
Li Y, Li N, Shi J. et al. Involvement of glutathione depletion in selective cytotoxicity of oridonin to p53-mutant esophageal squamous carcinoma cells. Front Oncol 2020; 9: 1525.
[http://dx.doi.org/10.3389/fonc.2019.01525 ] [PMID: 32010620]
[35]
Chen J, Lou Q, He L. et al. Reduced-gliotoxin induces ROS-mediated anoikis in human colorectal cancer cells. Int J Oncol 2018; 52(3): 1023-32.
[http://dx.doi.org/10.3892/ijo.2018.4264 ] [PMID: 29393399]
[36]
Manh Hung L, Song Y, Cho S. Effects of the combination of gliotoxin and adriamycin on the adriamycin-resistant non-small-cell lung cancer A549 cell line. Mar Drugs 2018; 16(4): 105.
[http://dx.doi.org/10.3390/md16040105 ] [PMID: 29584673]
[37]
Xie W, Huang P, Wu B. et al. Clinical significance of LOXL4 expression and features of LOXL4-associated protein-protein interaction network in esophageal squamous cell carcinoma. Amino Acids 2019; 51(5): 813-28.
[http://dx.doi.org/10.1007/s00726-019-02723-4 ] [PMID: 30900087]
[38]
Zhang E, Han L, Yin D. et al. H3K27 acetylation activated-long non-coding RNA CCAT1 affects cell proliferation and migration by regulating SPRY4 and HOXB13 expression in esophageal squamous cell carcinoma. Nucleic Acids Res 2017; 45(6): 3086-101.
[http://dx.doi.org/10.1093/nar/gkw1247 ] [PMID: 27956498]
[39]
Seibt TM, Proneth B, Conrad M. Role of GPX4 in ferroptosis and its pharmacological implication. Free Radic Biol Med 2019; 133: 144-52.
[http://dx.doi.org/10.1016/j.freeradbiomed.2018.09.014 ] [PMID: 30219704]
[40]
Koppula P, Zhuang L, Gan B. Cystine transporter SLC7A11/xCT in cancer: Ferroptosis, nutrient dependency, and cancer therapy. Protein Cell 2021; 12(8): 599-620.
[http://dx.doi.org/10.1007/s13238-020-00789-5 ] [PMID: 33000412]
[41]
Ajoolabady A, Aslkhodapasandhokmabad H, Libby P. et al. Ferritinophagy and ferroptosis in the management of metabolic diseases. Trends Endocrinol Metab 2021; 32(7): 444-62.
[http://dx.doi.org/10.1016/j.tem.2021.04.010 ] [PMID: 34006412]
[42]
Kang S, Lee E. Pharmaceutical composition for preventing or treating solid cancer, containing epidithiodioxopiperazine derivative or pharmaceutically acceptable salts thereof. US Patent 20160222031, 2016.
[43]
Amigorena S, Piaggio E, Niborski L. Inhibitor of SUV39H1 histone methyltransferase for use in cancer combination therapy. US Patent 20200157225, 2020.

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