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Electrophilic reactive aldehydes as a therapeutic target in colorectal cancer prevention and treatment

Oncogene volume 42, pages 1685–1691 (2023)Cite this article

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Abstract

Colorectal cancer (CRC) is a major health problem worldwide. Dicarbonyl electrophiles, such as isolevuglandins (isoLGs), are generated from lipid peroxidation and form covalent adducts with amine-containing macromolecules. We have shown high levels of adducts of isoLGs in colonic epithelial cells of patients with CRC. We thus investigated the role of these reactive aldehydes in colorectal cancer development. We found that 2-hydroxybenzylamine (2-HOBA), a natural compound derived from buckwheat seeds that acts as a potent scavenger of electrophiles, is bioavailable in the colon of mice after supplementation in the drinking water and does not affect the colonic microbiome. 2-HOBA reduced the level of isoLG adducts to lysine as well as tumorigenesis in models of colitis-associated carcinogenesis and of sporadic CRC driven by specific deletion of the adenomatous polyposis coli gene in colonic epithelial cells. In parallel, we found that oncogenic NRF2 activation and signaling were decreased in the colon of 2-HOBA-treated mice. Additionally, the growth of xenografted human HCT116 CRC cells in nude mice was significantly attenuated by 2-HOBA supplementation. In conclusion, 2-HOBA represents a promising natural compound for the prevention and treatment of CRC.

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Fig. 1: Effect of 2-HOBA on inflammation-mediated colon carcinogenesis.
Fig. 2: Effect of 2-HOBA on a model of sporadic colorectal cancer.
Fig. 3: Regulation of NRF2 activation by electrophiles.
Fig. 4: Treatment with 2-HOBA in mice with human xenografts.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was funded by NIH grants R41CA257262 (KTW and JAR), R01DK128200 (KTW), P01CA116087 (KTW); Department of Defense grant W81XWH-18-1-0301 (KTW); Veterans Affairs Merit Review grants I01CX002171 (KTW) and I01BX004366 (LAC); Senior Research Award 703003 from the Crohn’s and Colitis Foundation (KTW and APG); the Thomas F. Frist Sr. Endowment (K.T.W.); and the Vanderbilt Center for Mucosal Inflammation and Cancer (KTW). Histopathology studies were supported in part by the Tissue Morphology Subcore of the Translational Analysis Core of NIH grant P30DK058404.

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Authors and Affiliations

  1. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Alain P. Gobert, Mohammad Asim, Thaddeus M. Smith, Kamery J. Williams, Daniel P. Barry, Margaret M. Allaman, Kara M. McNamara, Caroline V. Hawkins, Alberto G. Delgado, M. Blanca Piazuelo, Lori A. Coburn & Keith T. Wilson

  2. Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, USA

    Alain P. Gobert, M. Blanca Piazuelo, M. Kay Washington, Lori A. Coburn & Keith T. Wilson

  3. Program in Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA

    Kara M. McNamara, Lori A. Coburn & Keith T. Wilson

  4. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA

    Shilin Zhao

  5. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA

    M. Kay Washington & Keith T. Wilson

  6. Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA

    Lori A. Coburn & Keith T. Wilson

  7. MTI BioTech Inc., Iowa State University Research Park, Ames, IA, USA

    John A. Rathmacher

  8. Department of Animal Science, Iowa State University, Ames, IA, USA

    John A. Rathmacher

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  1. Alain P. Gobert
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Contributions

APG was responsible for conceptualization, investigation, formal analysis, creation of the figures, writing the original draft, review and editing the manuscript, and funding acquisition. MA, TMS, KJW, DPB, MMA, KMM, CVH, AGD performed the experiments. SZ was responsible for data curation and formal analysis of the colonic microbiome. MBP analyzed the immunostaining. MKW performed the formal analysis of the histology. LAC performed the experiments and reviewed and edited the manuscript. JAR was responsible for conceptualization, formal analysis, review and editing the manuscript, and funding acquisition. KTW was responsible for conceptualization, review and editing the manuscript, and funding acquisition.

Corresponding author

Correspondence to Keith T. Wilson.

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Competing interests

APG and KTW are named inventors on a Vanderbilt University patent application for the use of electrophile scavengers. In addition, APG and KTW are named on a licensing agreement between Vanderbilt University and MTI Biotech for the future use of electrophile scavengers. All other authors have declared that no conflict of interest exists. JAR is an employee of MTI BioTech and is listed as an inventor on 2-HOBA patent applications. MTI BioTech intends to market/license 2-HOBA for commercial purposes.

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Gobert, A.P., Asim, M., Smith, T.M. et al. Electrophilic reactive aldehydes as a therapeutic target in colorectal cancer prevention and treatment. Oncogene 42, 1685–1691 (2023). https://doi.org/10.1038/s41388-023-02691-w

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  • DOI: https://doi.org/10.1038/s41388-023-02691-w

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