CoChat
Sign Up
Cited by 23Autophagy in Disease and TherapyMetabolism, Diabetes, and CancerCancer, Hypoxia, and Metabolism

Itraconazole improves survival outcomes in patients with colon cancer by inducing autophagic cell death and inhibiting transketolase expression

Open access
Shen, Pei-Wen, Chou, Yu-Mei, Li, Chia-Ling, Liao, En-Chih, Huang, Hung-Sen, Yin, Chun-Hao, Chen, Chien-Liang, Yu, Sheng-Jie·2021·Oncology Letters
DOI 10.3892/ol.2021.13029PMC PMC8442143
Open this paper in CoChat — free accountOpen PDF

Abstract

The incidence of colon cancer continues to increase annually, and it is the leading cause of cancer‑associated mortality worldwide. Altering cell metabolism and inducing autophagic cell death have recently emerged as novel strategies in preventing tumor growth. Autophagy plays an essential role in energy production by degrading damaged cellular components and is also associated with tumor proliferation suppression. Itraconazole is an FDA‑approved drug used as an antifungal medication and has been reported to induce autophagic cell death in breast cancer. However, the effects of itraconazole on cell metabolism and induction of apoptosis in colon cancer remain unclear. The present study analyzed extensive data from patients diagnosed with colon cancer using itraconazole between January 2011 and December 2015, from the Taiwanese National Health Insurance Research Database. The underlying molecular mechanisms of itraconazole in autophagy‑induced cell death were also investigated. The results demonstrated that the 5‑year survival rate was significantly higher in patients with colon cancer who received itraconazole treatment. In addition, itraconazole decreased the viability and cell colony formation, and induced cleaved caspase‑3 expression and G1 cell cycle arrest of COLO 205 and HCT 116 cells. Notably, itraconazole induced autophagy by enhancing LC3B and p62 expression. Following LC3 knockdown, the viability of itraconazole‑treated COLO 205 and HCT 116 cells notably improved. Taken together, the results of the present study suggest that itraconazole may have a beneficial effect on patients with colon cancer, and its underlying molecular mechanisms may be associated with the induction of autophagic cell death.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3892/ol.2021.13029

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

  • ITZ caused cleaved caspase-3 expression and G1 cell cycle arrest in COLO 205 and HCT 116 cells, while also reducing viability and cell colony formation.

    “Furthermore, ITZ caused cleaved caspase-3 expression and G1 cell cycle arrest in COLO 205 and HCT 116 cells, while also reducing viability and cell colony formation.”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [71]

    The Results (page not specified) report increased cleaved caspase-3, G1 arrest, and reduced viability after itraconazole treatment in COLO 205 and HCT 116 cells. The claim about reduced colony formation is not supported: the Discussion (page not specified) says a colony-formation assay could not be performed for both cell lines because HCT 116 proliferated inefficiently in matrix gel. (LLM, conf=0.92)

    Experimental — accuracy not yet measured

  • Patients with colon cancer treated with ITZ had a considerably greater 5 year survival rate.

    “The findings showed that patients with colon cancer treated with ITZ had a considerably greater 5 year survival rate.”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [71]

    The Results report a significantly higher 5-year survival rate on the Kaplan–Meier comparison, but the analysis was specifically of patients with late-stage colon cancer who received chemotherapy. The claim omits that restriction and implies the finding applies to patients with colon cancer generally. The adjusted mortality-risk estimate also did not reach statistical significance (P=0.067). (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • ITZ increased the expression of p62 and LC3B, which in turn caused autophagy.

    “Notably, ITZ increased the expression of p62 and LC3B, which in turn caused autophagy.”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [71]

    The Results section (‘Itraconazole induces autophagy in colon cancer’) reports increased LC3B and p62 expression after itraconazole treatment and concludes that itraconazole can induce autophagy. The Discussion likewise says p62 expression and autophagy both increased, but does not establish that the increased expression itself caused autophagy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • ITZ may benefit colon cancer patients, and the underlying molecular mechanisms may be linked to the triggering of autophagic cell death.

    “When combined, the study's findings imply that ITZ may benefit colon cancer patients, and that the underlying molecular mechanisms of the drug may be linked to the triggering of autophagic cell death.”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [71]

  • The viability of ITZ-treated COLO 205 and HCT 116 cells significantly increased after LC3 knockdown.

    “The viability of ITZ-treated COLO 205 and HCT 116 cells significantly increased after LC3 knockdown.”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [71]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 43

  1. [1]Miller KD Siegel RL Lin CC Mariotto AB Kramer JL Rowland JH Stein KD Alteri R Jemal A Cancer treatment and survivorship statistics, 2016 CA Cancer J Clin 66 271 289 2016 10.3322/caac.21349 27253694 · DOI · Paper page
  2. [2]Marisa L de Reyniès A Duval A Selves J Gaub MP Vescovo L Etienne-Grimaldi MC Schiappa R Guenot D Ayadi M Gene expression classification of colon cancer into molecular subtypes: Characterization, validation, and prognostic value PLoS Med 10 e1001453 2013 10.1371/journal.pmed.1001453 23700391 PMC3660251 · DOI · Paper page
  3. [3]Färkkilä N Torvinen S Sintonen H Saarto T Järvinen H Hänninen J Taari K Roine RP Costs of colorectal cancer in different states of the disease Acta Oncol 54 454 462 2015 10.3109/0284186X.2014.985797 25519708 · DOI
  4. [4]Aiello P Sharghi M Mansourkhani SM Ardekan AP Jouybari L Daraei N Peiro K Mohamadian S Rezaei M Heidari M Medicinal plants in the prevention and treatment of colon cancer Oxid Med Cell Longev 2019 2075614 2019 10.1155/2019/2075614 32377288 PMC7187726 · DOI
  5. [5]Yang Yp Hu Lf Zheng Hf Mao Cj Hu Wd Xiong Kp Wang F Liu Cf Application and interpretation of current autophagy inhibitors and activators Acta Pharmacol Sin 34 625 635 2013 10.1038/aps.2013.5 23524572 PMC4002883 · DOI
  6. [6]Onorati AV Dyczynski M Ojha R Amaravadi RK Targeting autophagy in cancer Cancer 124 3307 3318 2018 10.1002/cncr.31335 29671878 PMC6108917 · DOI
  7. [7]Islam MA Sooro MA Zhang P Autophagic regulation of p62 is critical for cancer therapy Int J Mol Sci 19 1405 2018 10.3390/ijms19051405 29738493 PMC5983640 · DOI
  8. [8]Lauren P The two histological main types of gastric carcinoma: Diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification Acta Pathol Microbiol Scand 64 31 49 1965 10.1111/apm.1965.64.1.31 14320675 · DOI
  9. [9]Jin S Wei J You L Liu H Qian W Autophagy regulation and its dual role in blood cancers: A novel target for therapeutic development (Review) Oncol Rep 39 2473 2481 2018 29658589
  10. [10]Huang F Wang BR Wang YG Role of autophagy in tumorigenesis, metastasis, targeted therapy and drug resistance of hepatocellular carcinoma World J Gastroenterol 24 4643 4651 2018 10.3748/wjg.v24.i41.4643 30416312 PMC6224467 · DOI
  11. [11]Xiang Y Zhao J Zhao M Wang K Allicin activates autophagic cell death to alleviate the malignant development of thyroid cancer Exp Ther Med 15 3537 3543 2018 29545880 PMC5841025
  12. [12]Stepanova NG Demcheva MV Formation of a pentose phosphate cycle metabolite, erythrose-4-phosphate, from initial compounds of glycolysis by transketolase from the rat liver Biokhimiia 52 1907 1913 1987 (In Russian) 3440115
  13. [13]Warburg O On the origin of cancer cells Science 123 309 314 1956 10.1126/science.123.3191.309 13298683 · DOI · Paper page
  14. [14]Qin Z Xiang C Zhong F Liu Y Dong Q Li K Shi W Ding C Qin L He F Transketolase (TKT) activity and nuclear localization promote hepatocellular carcinoma in a metabolic and a non-metabolic manner J Exp Clin Cancer Res 38 154 2019 10.1186/s13046-019-1131-1 30971297 PMC6458711 · DOI
  15. [15]Ricciardelli C Lokman NA Cheruvu S Tan IA Ween MP Pyragius CE Ruszkiewicz A Hoffmann P Oehler MK Transketolase is upregulated in metastatic peritoneal implants and promotes ovarian cancer cell proliferation Clin Exp Metastasis 32 441 455 2015 10.1007/s10585-015-9718-1 25895698 · DOI
  16. [16]Chao YK Peng TL Chuang WY Yeh CJ Li YL Lu YC Cheng AJ Transketolase serves a poor prognosticator in esophageal cancer by promoting cell invasion via epithelial-mesenchymal transition J Cancer 7 1804 1811 2016 10.7150/jca.15467 27698919 PMC5039363 · DOI
  17. [17]Hu LH Yang JH Zhang DT Zhang S Wang L Cai PC Zheng JF Huang JS The TKTL1 gene influences total transketolase activity and cell proliferation in human colon cancer LoVo cells Anticancer Drugs 18 427 433 2007 10.1097/CAD.0b013e328013d99e 17351395 · DOI
  18. [18]Cao L Hong W Cai P Xu C Bai X Zhao Z Huang M Jin J Cryptotanshinone strengthens the effect of gefitinib against non-small cell lung cancer through inhibiting transketolase Eur J Pharmacol 890 173647 2021 10.1016/j.ejphar.2020.173647 33049304 · DOI
  19. [19]Bhatia A Kanish B Badyal DK Kate P Choudhary S Efficacy of oral terbinafine versus itraconazole in treatment of dermatophytic infection of skin-A prospective, randomized comparative study Indian J Pharmacol 51 116 119 2019 10.4103/ijp.IJP_578_17 31142947 PMC6533924 · DOI
  20. [20]Pantziarka P Sukhatme V Bouche G Meheus L Sukhatme VP Repurposing drugs in oncology (ReDO)-itraconazole as an anti-cancer agent Ecancermedicalscience 9 521 2015 10.3332/ecancer.2015.521 25932045 PMC4406527 · DOI
  21. [21]Choi CH Ryu JY Cho YJ Jeon HK Choi JJ Ylaya K Lee YY Kim TJ Chung JY Hewitt SM The anti-cancer effects of itraconazole in epithelial ovarian cancer Sci Rep 7 6552 2017 10.1038/s41598-017-06510-7 28747628 PMC5529373 · DOI · Paper page
  22. [22]Liu R Li J Zhang T Zou L Chen Y Wang K Lei Y Yuan K Li Y Lan J Itraconazole suppresses the growth of glioblastoma through induction of autophagy: Involvement of abnormal cholesterol trafficking Autophagy 10 1241 1255 2014 10.4161/auto.28912 24905460 PMC4203550 · DOI · Paper page
  23. [23]Rudin CM Brahmer JR Juergens RA Hann CL Ettinger DS Sebree R Smith R Aftab BT Huang P Liu JO Phase 2 study of pemetrexed and itraconazole as second-line therapy for metastatic nonsquamous non-small-cell lung cancer J Thorac Oncol 8 619 623 2013 10.1097/JTO.0b013e31828c3950 23546045 PMC3636564 · DOI
  24. [24]Antonarakis ES Heath EI Smith DC Rathkopf D Blackford AL Danila DC King S Frost A Ajiboye AS Zhao M Repurposing itraconazole as a treatment for advanced prostate cancer: A noncomparative randomized phase II trial in men with metastatic castration-resistant prostate cancer Oncologist 18 163 173 2013 10.1634/theoncologist.2012-314 23340005 PMC3579600 · DOI · Paper page
  25. [25]Wang X Wei S Zhao Y Shi C Liu P Zhang C Lei Y Zhang B Bai B Huang Y Zhang H Anti-proliferation of breast cancer cells with itraconazole: Hedgehog pathway inhibition induces apoptosis and autophagic cell death Cancer Lett 385 128 136 2017 10.1016/j.canlet.2016.10.034 27810405 · DOI
  26. [26]Hsieh CY Su CC Shao SC Sung SF Lin SJ Yang YH Lai EC Taiwan's national health insurance research database: Past and future Clin Epidemiol 11 349 358 2019 10.2147/CLEP.S196293 31118821 PMC6509937 · DOI
  27. [27]Lin CC Lai MS Syu CY Chang SC Tseng FY Accuracy of diabetes diagnosis in health insurance claims data in Taiwan J Formos Med Assoc 104 157 163 2005 15818428
  28. [28]Edge SB Compton CC The American joint committee on cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM Ann Surg Oncol 17 1471 1474 2010 10.1245/s10434-010-0985-4 20180029 · DOI
  29. [29]Zonoobi E Saeedfar K Pourdowlat G Masjedi MR Behmanesh M The study of IL-10 and IL-17A genes expression in patients with different stages of asthma: A case-control study Tanaffos 17 146 154 2018 30915130 PMC6428381
  30. [30]Runwal G Stamatakou E Siddiqi FH Puri C Zhu Y Rubinsztein DC LC3-positive structures are prominent in autophagy-deficient cells Sci Rep 9 10147 2019 10.1038/s41598-019-46657-z 31300716 PMC6625982 · DOI · Paper page
  31. [31]Yun CW Lee SH The roles of autophagy in cancer Int J Mol Sci 19 3466 2018 10.3390/ijms19113466 30400561 PMC6274804 · DOI · Paper page
  32. [32]Deng H Huang L Liao Z Liu M Li Q Xu R Itraconazole inhibits the Hedgehog signaling pathway thereby inducing autophagy-mediated apoptosis of colon cancer cells Cell Death Dis 11 539 2020 10.1038/s41419-020-02742-0 32681018 PMC7367825 · DOI
  33. [33]Whitburn J Edwards CM Sooriakumaran P Metformin and prostate cancer: A new role for an old drug Curr Urol Rep 18 46 2017 10.1007/s11934-017-0693-8 28444639 PMC5405102 · DOI
  34. [34]Bellmann R Smuszkiewicz P Pharmacokinetics of antifungal drugs: Practical implications for optimized treatment of patients Infection 45 737 779 2017 10.1007/s15010-017-1042-z 28702763 PMC5696449 · DOI
  35. [35]Lan K Yan R Zhu K Li W Xu Z Dang C Li K Itraconazole inhibits the proliferation of gastric cancer cells in vitro and improves patient survival Oncol Lett 16 3651 3657 2018 30127974 PMC6096255
  36. [36]Wang W Dong X Liu Y Ni B Sai N You L Sun M Yao Y Qu C Yin X Ni J Itraconazole exerts anti-liver cancer potential through the Wnt, PI3K/AKT/mTOR, and ROS pathways Biomed Pharmacother 131 110661 2020 10.1016/j.biopha.2020.110661 32942154 · DOI
  37. [38]Alhakamy NA Md S Repurposing itraconazole loaded PLGA nanoparticles for improved antitumor efficacy in non-small cell lung cancers Pharmaceutics 11 685 2019 10.3390/pharmaceutics11120685 31888155 PMC6955961 · DOI
  38. [39]Zheng J Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review) Oncol Lett 4 1151 1157 2012 10.3892/ol.2012.928 23226794 PMC3506713 · DOI
  39. [40]Gill KS Fernandes P O'Donovan TR McKenna SL Doddakula KK Power DG Soden DM Forde PF Glycolysis inhibition as a cancer treatment and its role in an anti-tumour immune response Biochim Biophys Acta 1866 87 105 2016 27373814
  40. [41]Qu X Yu J Bhagat G Furuya N Hibshoosh H Troxel A Rosen J Eskelinen EL Mizushima N Ohsumi Y Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene J Clin Invest 112 1809 1820 2003 10.1172/JCI20039 14638851 PMC297002 · DOI · Paper page
  41. [42]Choi AMK Ryter SW Levine B Autophagy in human health and disease New Engl J Med 368 651 662 2013 10.1056/NEJMra1205406 23406030 · DOI · Paper page
  42. [43]Chu CW Ko HJ Chou CH Cheng TS Cheng HW Liang YH Lai YL Lin CY Wang C Loh JK Thioridazine enhances P62-mediated autophagy and apoptosis through wnt/beta-catenin signaling pathway in glioma cells Int J Mol Sci 20 473 2019 10.3390/ijms20030473 30678307 PMC6386927 · DOI
  43. [44]Bjørkøy G Lamark T Brech A Outzen H Perander M Overvatn A Stenmark H Johansen T p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death J Cell Biol 171 603 614 2005 10.1083/jcb.200507002 16286508 PMC2171557 · DOI · Paper page

Cited by

Sorted by citations

Authors
Shen, P.-W., Chou, Y.-M., Li, C.-L., Liao, E.-C., Huang, H.-S., Yin, C.-H., Chen, C.-L., & Yu, S.-J.
Affiliations
  • Kaohsiung Veterans General Hospital (TW)
  • Taichung Veterans General Hospital (TW)
  • Mackay Medical University (TW)
Corresponding author
Yu, Sheng-Jie
ORCID
Venue
Oncology Letters
Publisher
Spandidos Publications
Published
2021-09-08
Volume
22
Issue
5
Pages
768-768
ISSN
  • 1792-1074 (ISSN-L)
  • 1792-1082
DOI
10.3892/ol.2021.13029
PMC
PMC8442143
OpenAlex
W3196533889
Cited by
23
References
2
Citations by year
2026: 3 · 2025: 5 · 2024: 8 · 2023: 3 · 2022: 4
FWCI
2.70
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Oncology Letters (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
Kaohsiung Veterans General Hospital (VGHKS109-D04-1, VGHKS109-180)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords
itraconazole, colon cancer, autophagic cell death, transketolase, LC3B, p62, caspase-3, G1 cell cycle arrest, cell viability, survival outcomes, drug repurposing

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