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Published in final edited form as: Oncogene. 2023 Apr 10;42(20):1685–1691. doi: 10.1038/s41388-023-02691-w

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

Alain P Gobert 1,2, Mohammad Asim 1, Thaddeus M Smith 1, Kamery J Williams 1, Daniel P Barry 1, Margaret M Allaman 1, Kara M McNamara 1,3, Caroline V Hawkins 1, Alberto G Delgado 1, Shilin Zhao 4, M Blanca Piazuelo 1,2, M Kay Washington 2,5, Lori A Coburn 1,2,3,6, John A Rathmacher 7,8, Keith T Wilson 1,2,3,5,6
PMCID: PMC10182918  NIHMSID: NIHMS1892542  PMID: 37037901

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 was 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.

INTRODUCTION

Colorectal cancer (CRC) is the third most diagnosed cancer worldwide, with two million new cases per year and this incidence will certainly continue to rise in the next decades, notably in countries with the largest populations and in younger adults [1, 2]. Moreover, CRC is the second leading cause of death by cancer globally, accounting for over one million deaths yearly [2]. This leads to the need for colonoscopic screening and frequent colonoscopic surveillance in patients with adenomas or chronic colitis and progression to surgical resections with discovery of CRC. New therapies that could be safe, effective, inexpensive, and rationally-based are needed to reduce the risk for neoplastic transformation in the colon and for adjunctive therapy for existing CRC.

The genetic alterations leading to CRC, also known as the classical Vogelgram, have been well characterized [3]. Principally, the generation of early adenomas results from germline or somatic mutations in the gene encoding for the adenomatous polyposis coli (APC) protein, whose loss of function allows for the uncontrolled activation of β-catenin. This transcriptional activator induces in turn the expression of genes encoding for the Myc proto-oncogene protein (MYC) [4], a transcription factor controlling proliferation/differentiation and the production of reactive oxygen species (ROS) [5] or the enzyme prostaglandin G/H synthase 2 [6] that generates prostaglandin H2, the precursor of all prostaglandins and thromboxanes. Additionally, patients with inflammatory bowel disease (IBD) have a high cumulative risk of developing colitis-associated carcinoma (CAC) [7] and exhibit an increase of ROS and prostaglandin synthesis in the colonic mucosa [8].

The nonenzymatic rearrangement of prostaglandins and/or the oxidative degradation of lipids lead to the formation of highly reactive aldehydes, termed dicarbonyl electrophiles, including isolevuglandins (isoLGs), malondialdehyde, 4-hydroxy-nonenal, 4-oxo-nonenal, and methylglyoxal [9]. These strong oxidants form irreversible covalent adducts with amines present in nucleic acid bases, notably deoxycytidine, deoxyadenosine, and deoxyguanosine [10], and also in lysine residues of proteins such as histones [11, 12]. As the intermediates in the formation of these adducts of DNA and histones are also highly electrophilic, they can produce DNA-DNA and histone-DNA crosslinks [12]. Therefore, these molecular alterations lead to changes in cell signaling, somatic genomic abnormalities, and epigenetic alterations [12, 13], which are critical events for carcinogenesis and cancer development. Of importance, we found high levels of nuclear adducts of isoLGs to lysine (isoLG-lysyl) in colonic epithelial cells (CECs) from patients with active colitis, dysplasia, or CAC, as well as in adenomatous polyps with areas of high-grade dysplasia, and in CRC tumor tissues [14]. Similarly, the concentration of the electrophile malondialdehyde is increased in primary colon tumors compared to normal colon [15] and in the plasma of CRC patients versus normal individuals [16]. Moreover, an experimental scavenger of electrophiles prevents tumorigenesis in a murine model of CAC [14].

The natural product 2-hydroxybenzylamine (2-HOBA) is derived from buckwheat seeds [17] and reacts with all electrophiles, except 4-hydroxy-nonenal that reacts with soft nucleophiles such as cysteine, at a rate 3 orders of magnitude faster than with lysine, thus preventing adduct formation with macromolecules [9]. It is not toxic or mutagenic [18–20] and protects mice from oxidative damage in models of hypertension [21, 22], atherosclerotic cardiovascular disease [23], and Alzheimer’s disease [24]. Since two Phase 1 clinical trials have demonstrated its safety in humans [25, 26], 2-HOBA is well-positioned as a chemopreventive agent for the development of neoplastic transformation in the colon, notably in high-risk populations, such as IBD patients, individuals with congenital APC mutation, and patients with a history of high-risk/advanced adenomas. In this context, our goal was to test the effect of 2-HOBA on colon carcinogenesis in models of CAC and sporadic CRC. We also sought to determine the efficacy of 2-HOBA on altering the growth of existing tumors in a model of human CRC cell xenografts.

RESULTS

Tumorigenesis is reduced by 2-HOBA in a model of CAC

We first tested the effect of 2-HOBA on colon carcinogenesis in C57BL/6 mice treated with azoxymethane (AOM) and dextran sulfate sodium (DSS) (Fig. 1A), as a reliable model of inflammation-driven colon carcinogenesis [14]. Mice that were given DSS lost weight significantly during each cycle compared to untreated mice, but there was no difference between animals treated or not with 2-HOBA (Fig. 1B). At the end of the experiment, we did not detect 2-HOBA in the colon of naïve mice or of those treated with AOM-DSS only (Fig. 1C; Supplementary Fig. 1). In contrast, 2-HOBA was found in the colon of animals that were given this scavenger, treated or not with AOM-DSS (Fig. 1C; Supplementary Fig. 1), demonstrating that per os treatment with 2-HOBA efficiently increases its concentration in the colon. In AOM-DSS-treated mice, 2-HOBA had no effect on the number of tumors in the colon (Fig. 1D). However, mice that were given 2-HOBA had a significant reduction in tumor size (Fig. 1E–F) and total tumor burden per colon (Fig. 1G). The reduced tumor size in the 2-HOBA-treated group was confirmed microscopically by the analysis of H&E staining (Fig. 1H). The level of histologic inflammation in the non-tumor areas was not affected by 2-HOBA supplementation (Fig. 1I).

Fig. 1. Effect of 2-HOBA on inflammation-mediated colon carcinogenesis.

Fig. 1.

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A C57BL6 mice were treated with AOM (12.5 mg.kg–1)-DSS (4%) and were given 2-HOBA (1 mg.ml–1) throughout the experiments, except during DSS treatment. B Body weights were measured weekly and are depicted as percentage of initial body weight; ***P < 0.001 and ****P < 0.0001 compared to AOM-DSS-treated mice in the control and 2-HOBA groups. C After 56 days, colons were removed and the concentration of 2-HOBA was measured by LC/ESI/MS/MS. D The number of tumors was counted. E-F tumor size was assessed by the average tumor size per mouse (E) and as a percent of total tumors (n = 106 tumors for the AOM-DSS group and n = 96 for AOM-DSS + 2-HOBA; F). G Tumor burden was calculated. H Representative images of H&E staining and tumors are surrounded by dotted lines. The scale bars correspond to 200 μm. I The histological injury score was calculated from the H&E staining. In figures with dot plots, P was determined by two-way ANOVA and Tukey test in B, one-way ANOVA and Tukey test in C, or Student’s t test (D, E, G, I); we also used Chi-Square for the contingency analysis (F).

2-HOBA dampens the immune response in AOM-DSS-induced tumors

We then assessed the effect of 2-HOBA on colonic mucosal immune gene expression during AOM-DSS treatment. In the non-tumor area of AOM-DSS-treated mice, the genes Nos2, Cxcl1, and Ifng were significantly upregulated compared to control animals, and there was no difference in the level of expression with 2-HOBA (Supplementary Fig. 2). Strikingly, these 3 genes plus Tnf, Il1b, and Il17 were induced in the tumors of mice treated with AOM-DSS (Supplementary Fig. 2). Unlike non-tumor areas, the expression of Nos2, Tnf, Cxcl1, and Ifng was significantly reduced in the tumors of mice that were given 2-HOBA (Supplementary Fig. 2).

2-HOBA limits tumorigenesis associated with Apc loss

To test the effect of 2-HOBA in a model of sporadic CRC, we used transgenic C57BL/6 mice with tamoxifen (TAM)-inducible disruption of Apc using the intestinal epithelial cell-specific, caudal type homeobox 2 (CDX2) Cre driver (CDX2P-CreERT2;Apcfl/fl; Fig. 2A). Animals treated with TAM or TAM + 2-HOBA had significant body weight loss compared to sham treatment throughout the time course of the experiment (Fig. 2B). We detected 2-HOBA in the colon of CDX2P-CreERT2;Apcfl/fl mice supplemented with this scavenger, treated or not with TAM, but not in the tissues of mice not exposed to 2-HOBA (Fig. 2C; Supplementary Fig. 1). The number of tumors (Fig. 2D–E) and the tumor burden (Fig. 2F) observed in TAM-treated CDX2P-CreERT2;Apcfl/fl mice were significantly reduced by 2-HOBA supplementation. Further, we found that tumor burden was inversely correlated with 2-HOBA levels (Fig. 2G). Histology (Fig. 2H) highlighted fewer and smaller adenomas in the 2-HOBA-treated group, while the moderate inflammation of the non-tumor area was not affected (Fig. 2I).

Fig. 2. Effect of 2-HOBA on a model of sporadic colorectal cancer.

Fig. 2.

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A CDX2P-CreERT2;Apcfl/fl mice were treated or not with TAM (4.5 mg.kg–1) ± 2-HOBA (1 mg.ml–1). B Body weights were monitored weekly and are shown as percentage of initial body weight; *P < 0.05, **P < 0.01, and ****P < 0.0001 compared TAM-treated mice, and §P < 0.05, §§P < 0.01, and §§§§P < 0.0001 compared to TAM-treated mice in the 2-HOBA group. C 35 days after TAM injection, colonic levels of 2-HOBA were measured by LC/ESI/MS/MS. D-F Tumor number (D-E) and burden (F) were determined in the mid and distal colon. Note that there were no tumors in animals that did not receive TAM, treated or not with 2-HOBA. G Correlation plots comparing tumor burden (from Fig. 3F) and 2-HOBA concentrations (from Fig. 3C). H The H&E staining shows a large tumor with a complex growth pattern indicating high-grade dysplasia in the TAM group and two smaller tumors formed by densely packed neoplastic crypts with low-grade dysplasia; scale bar, 100 μm. I The inflammation score was determined by histologic assessment. P values were calculated by two-way ANOVA and Tukey test (B), one-way ANOVA and Tukey test (C), and Student’s t test (E, F, I). In (G), statistical analysis was performed using the Pearson correlation test.

The composition of the intestinal microbiota is not affected by 2-HOBA

We then considered the possibility that the protective role of 2-HOBA in colorectal carcinogenesis could be due to an effect on the intestinal microbiota. To test this hypothesis, we determined the gut microbiome of CDX2P-CreERT2;Apcfl/fl mice treated or not with 2-HOBA for 35 days. The total number of bacteria in the gut and the diversity of the microbial community, assessed by Simpson and Shannon indexes (Supplementary Fig. 3A–B), were not affected by 2-HOBA.

The colon microbiota of CDX2P-CreERT2;Apcfl/fl mice was dominated by the Bacteroidetes phylum (Supplementary Fig. 3C). Firmicutes and Proteobacteria were also detected in the microbiota in a proportion ranging from 5.8% to 14.1% (Supplementary Fig. 3C). Overall, the microbiome at the phylum level was similar in mice that were given 2-HOBA (Supplementary Fig. 3C; Supplementary Table 1).

At the genus level, Prevotella, Bacteroides, and Porphyromonadaceae were dominant in mice treated or not with 2-HOBA (Supplementary Fig. 3D). Similarly, the prevalence of the genus belonging to Firmicutes, such as Lachnospiraceae, and Proteobacteria, including Helicobacter and Parasutterella, was not altered by 2-HOBA supplementation (Supplementary Fig. 3D; Supplementary Table 1).

NRF2 activation is regulated by 2-HOBA

We have reported that isoLG-lysyl adducts are increased in the colon of mice treated with AOM-DSS and reduced by an experimental electrophile scavenger [14]. Next, we questioned whether the nutraceutical 2-HOBA has the same effect in mice with intestinal epithelial-specific Apc deletion. In the non-tumor areas, we observed that the frequency of cells exhibiting isoLG-lysyl adducts in the nuclei of CECs of TAM-treated mice was markedly enhanced compared to the control group (Fig. 3A). In TAM-treated mice, the nuclear staining was observed all along the crypts (Fig. 3A). There was less nuclear staining when animals with specific Apc deletion were given 2-HOBA (Fig. 3A). These observations were confirmed by the quantification on multiple mice per group, evidencing a significant increase of isoLG-lysyl adducts in CDX2P-CreERT2;Apcfl/fl mice + TAM that was reduced with 2-HOBA supplementation (Fig. 3B).

Fig. 3. Regulation of NRF2 activation by electrophiles.

Fig. 3.

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The colon of CDX2P-CreERT2;Apcfl/fl mice ± TAM (4.5 mg.kg–1) ± 2-HOBA (1 mg.ml–1) was immunostained with the D11 antibody, which detects isoLG-lysyl adducts (A) and the nuclear staining was quantified (B). Each dot represents a mouse, and 20 crypts per animal were assessed. Scale bars, 50 μm. C RNA was extracted from non-tumor areas (NT) or tumors (T) from CDX2P-CreERT2;Apcfl/fl mice ± TAM ± 2-HOBA, and gene expression was then measured by RT-real-time PCR. D The activation of NRF2 was assessed by immunofluorescence and the images are representatives of 3 animals per group. E Quantification of nuclear translocation of NRF2; each dot represents a mouse, and 5–10 crypts per animal were assessed. Scale bars, 50 μm. P values were calculated by two-way ANOVA and Tukey test (C) or Dunnett’s test (A, E).

To further understand the molecular mechanism by which dicarbonyl electrophiles support colon carcinogenesis, we first analyzed the expression of various genes well-known for their role in neoplasia. In the Apc deletion model, the genes encoding for the pro-inflammatory mediators IL-1β and CXCL1 were induced at the same level in tumors of TAM-treated mice ± 2-HOBA (Fig. 3C). The expression of the β-catenin target genes Myc, Mmp7, Axin2, Ccnd1, and Ptgs2 was similar in the tumors of mice receiving 2-HOBA or not (Fig. 3C). In contrast, the gene Hmox1, which is notably regulated by the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), was induced in the non-tumor and tumor areas of TAM-treated mice but was significantly less expressed in animals supplemented with 2-HOBA (Fig. 3C). Similarly, the NRF2-target gene Slc7a11 was downregulated in the tumors of mice that were given 2-HOBA compared to sham treatment (Fig. 3C). In this context, we sought to determine the activation of NRF2. We observed a strong nuclear translocation of NRF2 in CECs from mice treated with TAM compared to controls (Fig. 3D). However, there was less nuclear translocation in 2-HOBA-treated mice (Fig. 3D). This result was confirmed by the quantification of NRF2-postivite nuclei in CECs (Fig. 3E).

2-HOBA reduces human tumor development in a xenograft model

Our current data demonstrate that 2-HOBA dampens carcinogenesis. To test the effect of 2-HOBA on growth of established tumors, we used xenografts of HCT116 CRC cells in nude mice. 2-HOBA treatment in the drinking water was initiated after mice exhibited detectable tumors. First, we observed that 2-HOBA was bioavailable in the tumors of animals treated with this scavenger (Fig. 4A). The growth of tumors in 2-HOBA-treated nude mice was significantly slower compared to the sham group (Fig. 4B). At sacrifice, we confirmed that the xenografts from animals that were given 2-HOBA exhibited a smaller size (Fig. 4C) and therefore significantly less volume (Fig. 4D). The tumor growth inhibition rate was 42% at the end of the experiment. Lastly, we found a significant and inverse correlation between tumor volume and the concentration of 2-HOBA in the xenografts (Fig. 4E).

Fig. 4.

Fig. 4.

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Treatment with 2-HOBA in mice with human xenografts. Human CRC HCT116 cells were injected in the flank of nude mice. Animals were then treated or not with 2-HOBA (1 mg.ml–1). A The levels of 2-HOBA were measured in the tumors after 35 days. B Tumor volume was measured weekly in sham-treated (left panel) or 2-HOBA-treated (middle panel) mice. The right panel depicts mean ± SEM; the fixed effects (type III) P value (time and treatment) was calculated by two-way ANOVA and Tukey test. C-D On day 35, tumors were harvested (C), measured, and the volume was calculated (D). P was determined by the Student’s t test. Scale bar, 1 cm. E Correlation comparing tumor volume (from Fig. 5D) and 2-HOBA concentrations (from Fig. 5A, middle panel). Statistical analysis was performed using the Pearson correlation test.

DISCUSSION

CRC is a global public health problem worldwide. Systematic CRC screening has led to a reduction of the prevalence of CRC in older persons in developed countries, but in the last two decades the rate of CRC mortality in people less than 50 years-old has increased by more than 1% annually. In this context, strategies that can prevent malignant transformation are essential to manage the disease burden. In this report, we show that the scavenger of reactive aldehydes, 2-HOBA, is bioavailable in the colon as in other organs [27, 28], prevents nuclear accumulation of electrophile adducts in CECs, NRF2 activation and expression of NRF2-target oncogenes, and carcinogenesis in a murine model of genetically-mediated colon cancer. In addition, 2-HOBA reduced the growth of xenografts of human CRC cells, suggesting a potential efficacy to limit the development of established colorectal tumors. In addition, we found that 2-HOBA treatment does not impact the composition of the colonic microbiota; this finding provides a further rationale for the use of 2-HOBA in patients with high risk for CAC/CRC or treated for CRC since dysbiosis of the gut microbiota supports colon inflammation and carcinogenesis, and can also reduce the efficacy of cancer treatment by chemotherapy, radiotherapy, or immunotherapy [29].

Lipid peroxidation-derived compounds are synthesized in the colon during DSS colitis [30] and in AOM-DSS-treated mice [31]. In addition, studies have shown that patients with CRC exhibit reduced levels of glutathione and lower expression of enzymes involved in reactive aldehyde detoxification, such as glutathione S-transferases [16]. Interestingly, Apc mutation in mice is associated with increased number and redistribution farther up the crypt of aldehyde dehydrogenase-positive stem cells, but also with a reduction of the maturation of these cells along the neuroendocrine cell lineage [32, 33]. These data suggest that the fight against excessive dicarbonyl electrophiles is a physiological response to counteract oxidative injury. In this context, the enhanced generation of dicarbonyl electrophiles and the decreased ability to degrade them supports the use of electrophile scavengers, such as 2-HOBA, to dampen this potent oxidative stress. Providing further evidence of the deleterious role of electrophiles, repeated intraperitoneal injection of the aldehyde epoxyketooctadecenoic acid exacerbates AOM-DSS-induced tumorigenesis in mice [31].

The transcription factor NRF2 is a master regulator of the inducible expression of genes encoding for enzymes involved in detoxification of reactive oxygen species and aldehydes and is therefore activated by oxidative species including dicarbonyl electrophiles [34]. Herein, we observed that the nuclear translocation of NRF2 in CECs and the expression of NRF2-target genes are stimulated by Apc deletion and reduced by 2-HOBA treatment, suggesting that electrophiles may support colon carcinogenesis through a mechanism that involves this transcription factor. In fact, NRF2 is considered as an oncogene in different cancers due to the induction of genes involved in cell survival, proliferation, and repression of apoptosis. NRF2 is increased in CRC tissues and is associated with poor prognosis [35]. In mice, the study of the role of NRF2 in carcinogenesis has led to contradictory results; in the AOM-DSS model, deletion of Nfe2l2, which encodes NRF2, leads to increased tumorigenesis in BALB/C mice [36], but a reduction of tumor number in the C57BL/6 background [37]. Note that these studies were performed with mice with total knockout of NRF2. In this context, it would be interesting to decipher the specific role of NRF2 in CECs in colorectal carcinogenesis, notably mediated by lipid peroxidation products.

The use of classical antioxidants including N-acetylcysteine, vitamins, or selenium, have shown moderate or no effect on CRC development, recurrence, or treatment in the general population [38]. However, these antioxidants are not specific to lipid aldehyde species [9], which are potent oxidants of proteins and DNA. For example, N-acetylcysteine serves as an excellent scavenger of nitric oxide, hypochlorous acid, and hydroxyl radicals, whereas vitamin E acts in the defense against free radicals. Their rate constant of reactions with free radicals is 105-106 faster than with aldehydes [39]. Lastly, although oxidative and nitrosative species can lead to lipid peroxidation, dicarbonyl electrophiles can be generated through multiple sources. These data may explain the failure of classical antioxidants and provide a rationale for the use of a specific scavenger of all reactive aldehydes for the prevention and/or treatment of CRC.

In conclusion, 2-HOBA, which has been shown to be safe in humans, reduces colon tumorigenesis in murine models of CAC and sporadic CRC, as well as growth of human CRC tumor cells in xenografts in nude mice. Because 2-HOBA also prevents gastric carcinogenesis [28], this scavenger holds promise as a gastrointestinal cancer agent with a favorable safety profile. Thus, Phase 1 and ultimately Phase 2 trials are warranted in gastrointestinal cancers, including colorectal.

Supplementary Material

Supplementary Information

ACKNOWLEDGEMENTS

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

Footnotes

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.

DATA AVAILABILITY STATEMENT

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

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Information
NIHMS1892542-supplement-Supplementary_Information.docx (1.8MB, docx)

Data Availability Statement

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

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