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Cited by 51Cancer, Lipids, and MetabolismCancer, Hypoxia, and MetabolismLipid metabolism and biosynthesis

Proton pump inhibitors suppress DNA damage repair and sensitize treatment resistance in breast cancer by targeting fatty acid synthase

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Wang, Chao J., Li, Deren, Danielson, Jacob A., Zhang, Evan H., Dong, Zizheng, Miller, Kathy D., Li, Lang, Zhang, Jian-Ting +1 more·2021·Cancer Letters
DOI 10.1016/j.canlet.2021.03.026PMC PMC8167934
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Abstract

Human fatty acid synthase (FASN) is the sole cytosolic enzyme responsible for de novo lipid synthesis. FASN is essential for cancer cell survival and contributes to drug and radiation resistance by up-regulating DNA damage repair but not required for most non-lipogenic tissues. Thus, FASN is an attractive target for drug discovery. However, despite decades of effort in targeting FASN, no FASN inhibitors have been approved due to poor pharmacokinetics or toxicities. Here, we show that the FDA-approved proton pump inhibitors (PPIs) effectively inhibit FASN and suppress breast cancer cell survival. PPI inhibition of FASN leads to suppression of non-homologous end joining repair of DNA damages by reducing FASN-mediated PARP1 expression, resulting in apoptosis from oxidative DNA damages and sensitization of cellular resistance to doxorubicin and ionizing radiation. Mining electronic medical records of 6754 breast cancer patients showed that PPI usage significantly increased overall survival and reduced disease recurrence of these patients. Hence, PPIs may be repurposed as anticancer drugs for breast cancer treatments by targeting FASN to overcome drug and radiation resistance.

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  • PPIs mitigated resistance commonly seen with conventional chemotherapy drugs and radiation treatments.

    “Notably, these PPIs also mitigated resistance commonly seen with conventional chemotherapy drugs and radiation treatments.”

    From Drug repurposing for cancer therapy (2024) · cites this paper as [317]

    The Results section, “Lansoprazole and DNA-damaging treatments synergistically inhibit breast cancer cell survival” (page unavailable), reports that lansoprazole enhanced doxorubicin and ionizing-radiation effects in two breast cancer cell lines. The claim extends those findings to PPIs and conventional chemotherapy drugs generally; the passage tests one PPI and one chemotherapy drug. (LLM, conf=0.82)

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  • A study of 6754 breast cancer patients revealed that PPI use markedly improved overall survival rates and reduced the risk of disease recurrence.

    “Moreover, a study of 6754 breast cancer patients revealed that the use of PPIs not only markedly improved their overall survival rates but also reduced the risk of disease recurrence.317”

    From Drug repurposing for cancer therapy (2024) · cites this paper as [317]

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Research works printed but not linked: 31

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Authors
Wang, C. J., Li, D., Danielson, J. A., Zhang, E. H., Dong, Z., Miller, K. D., Li, L., Zhang, J.-T., & Liu, J.-Y.
Affiliations
  • Indiana University School of Medicine (US)
  • University of Toledo (US)
  • The Ohio State University (US)
Corresponding author
Zhang, Jian-Ting
ORCID
Venue
Cancer Letters
Publisher
Elsevier BV
Published
2021-07
Volume
509
Pages
1-12
ISSN
0304-3835 (ISSN-L)
DOI
10.1016/j.canlet.2021.03.026
PMC
PMC8167934
OpenAlex
W3149460283
Cited by
51
References
36
Citations by year
2026: 4 · 2025: 10 · 2024: 10 · 2023: 15 · 2022: 11 · 2021: 1
FWCI
3.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Letters (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
Funders
  • US Department of Defense (W81XWH -16-1-0030)
  • Breast Cancer Research Foundation
  • National Institutes of Health (R01 GM127656)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords
proton pump inhibitors, fatty acid synthase, breast cancer, drug resistance, radioresistance (biology), DNA repair, non-homologous end joining, PARP1, oxidative DNA damage, apoptosis, doxorubicin, drug repurposing, overall survival, electronic health records
MeSH terms
Poly (ADP-Ribose) Polymerase-1, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, DNA Damage, Doxorubicin, Drug Synergism, Enzyme Inhibitors, Female, Humans, Radiation Tolerance, Apoptosis, Drug Resistance, Neoplasm, Proton Pump Inhibitors, Fatty Acid Synthase, Type I, Data Mining, Electronic Health Records, Chemoradiotherapy, DNA End-Joining Repair, MCF-7 Cells, Lansoprazole

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