Inflammatory bowel disease-associated colorectal cancer (CACRC) is becoming more prevalent worldwide and presents at a younger age. IBD, as well as CACRC, is evolving worldwide, especially in newly industrialized countries. With an aging population, its compound prevalence suggests that CACRC could become an emerging global challenge. Although surveillance and chemoprevention for CACRC exist, sixty percent of patients with CACRC are asymptomatic upon detection and over fifty percent present with advanced disease; this eventually leads to less favorable outcomes compared to sporadic colorectal cancer (SCRC). To understand why, scientists profiled surgical pathology resections of colonic mucosal and submucosal layers from patients with IBD who had undergone pouch surgery, restorative proctocolectomy with ileal pouch–anal anastomosis (RPC-IPAA) [1]. A pool of exogenous/free hemoglobin alpha chains (HbαCs) in areas of active colitis was unexpectedly found. Furthermore, the HbαCs were produced through the action of immune infiltrating cells (macrophages) that promoted reactive oxygen species (ROS) in epithelial cells depleted of colonic tissue homogenate antioxidants (i.e., nuclear factor erythroid 2-related factor 2 (Nrf2), catalase (CAT) superoxide dismutase (SOD), and glutathione peroxide (GPx)). The antioxidants above are significant regulators of cytoprotective responses to oxidative stress and the primary cellular defense against cytotoxic effects of oxidative stress [2,3,4,5,6]. Intestinal mucosal damage in IBD involves reactive oxygen metabolites (ROMs). Endogenous antioxidant enzymes neutralize ROMs in a carefully balanced two-step pathway. First, SOD converts superoxide anion to hydrogen peroxide (H(2)O(2)). Then, hydrogen peroxide is neutralized to water by CAT or glutathione peroxidase (GPO) [1]. This indicates that exogenous/free HbαC has a physiological role in inducing ROS formation and DNAD and, if not attenuated, can trigger carcinogenesis [1].

Colorectal cancer (CRC) is often described as the “disease no one has to die from”, but approximately 50% of patients with CRC who undergo potentially curative surgery ultimately relapse and die, usually as a consequence of metastatic disease [9,10]. According to GLOBOCAN 2018 data, and the American Cancer Society, for both men and women in the United States of America, colorectal cancer (CRC) is the third main cause of cancer-related mortality in the world [11,12]. CRC is the deadliest cancer [13,14]. IBD is a known risk factor for developing CACRC [15]. IBD patients are at increased risk of CACRC due to long-standing chronic inflammation, genetic alterations, and epigenetic environmental factors [16,17,18]. Additionally, data indicate that CACRC may have evolved through a pathway of tumorigenesis distinct from that of SCRC.

Predominantly colonic IBD, the “colitides”, includes ulcerative colitis (UC) and Crohn’s colitis (CC), which are two heterogeneous, chronic relapsing and remitting gastrointestinal tract disorders in the colon [18,19,20,21,22]. Currently, both diseases affect approximately three million people in the United States. However, the incidence and prevalence of both are increasing worldwide, thus making them global emergent diseases with significant clinical challenges [22]. The global prevalence of IBD is currently evolving, approaching 90 cases/100,000 people [23], though awareness should be assessed in each of the geographical locations of the world [24,25]. North America and Canada have the highest rates of IBD in the world [26,27]. However, over the past three decades, the incidence of IBD in low-income countries has steadily risen. [26,28,29,30,31,32,33]. The burden/implication of IBD is discrete in various countries and locations, especially when contrasted/matched between low-income [34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49] and wealthy nations [50,51]. The estimated data suggest that 25 to 30 percent of cases of CD and 20 percent of patients with UC present during adolescence and young adulthood at the reproductive age [52,53,54,55,56,57,58,59,60,61]. The extent of racial/ethnic and regional differences in the prevalence of IBD in the United States remains largely unknown, warranting additional research [62,63]. However, IBD has predominantly affected white populations, particularly Ashkenazi Jews. But over the last three decades, IBD has “emerged” in minority communities [26,63,64,65,66,67,68]. The genesis of IBD is unknown, but is believed to be multifactorial [18,30,69,70]. It has been hypothesized that intestinal damage in UC and in CC is related both to increased oxygen-derived free radical production, mainly resulting from a respiratory burst of infiltrating phagocyte cells, and to a low concentration of endogenous antioxidant defense mechanisms. Indeed, neutrophils and monocytes in patients with active and/or fulminant IBD exhibit higher concentrations of oxygen-derived free radicals than in normal control samples [70,71,72,73]. Compared to other tissues, the gut is potentially more susceptible to oxidant injury/trauma, which can be exacerbated by the low concentration of antioxidant enzymes in epithelial cells, which contributes to the ROS cytotoxicity observed in the colons of patients with IBD [1,74]. IBD has no curative drug, often resulting in significant long-term comorbidity (1). The development of potential immunosuppressive therapies in IBD aims to achieve long, deep remission, but their effects on subsequent CACRC have yet to be established. However, studies have shown that the longer a person has had IBD, the higher their chance of developing CACRC [75,76,77]. An extensively referenced comprehensive meta-analysis of 19 longitudinal and cross-sectional studies with age-stratified data reported that the cumulative incidence of CACRC in UC is 2% after 10 years, 8% after 20 years, and 18% after 30 years of disease [78]. In contrast, other studies reported lower incidence rates accredited to, among other factors, the benefits of endoscopic monitoring surveillance and anti-inflammatory pharmaceutical chemoprophylaxis [79,80,81].

People who suffer from colonic IBD are at increased risk for developing CACRC [79,82]. All instances of CACRC are located in segments with colitis [75]. CACRC is one of the most severe complications of IBD, with a mortality rate of 10–15%, and the risk is 1.5–2.4-fold that in the general population [15,83]. The dysplasia of CACRC develops via a different pathway and mechanism in comparison to SCRC [15]. The well-established risk factors for CACRC are time scale and the extent of intestinal inflammatory lesions [15,75,84,85,86]. Genetic factors, coupled with the longevity of the persistent fulminant interdependent inflammatory process in the colonic mucosal layers, are believed to play a remarkable role in CACRC carcinogenesis, and consequently, inflammatory action could decrease this continuous process of inflammation associated with carcinogenesis [87,88,89]. Survivability depends on adherence to colonoscopic surveillance, and early elective colectomy is recommended [75,90,91]. However, some oncologic analyses provide positive results after curative surgeries in patients with CACRC [89,92]. This warrants continuous surveillance to assess postcolectomy safety [75,90,93].

The prevalence of CACRC development is identical for patients with UC and CC [94,95,96,97], as is the quantitative exogenous HbαC between the two colitides [1]. This timely review was conducted to summarize and determine the efficacy and pharmaceutical safety of Fenton Reaction mitigation as a preventive measure for CACRC.

The tight junction is an intricate intercellular junction found in epithelial and endothelial cells that is accountable for the genesis of functional epithelial and endothelial barriers that synchronize the passage of cells and solutes through the paracellular space [98]. Patients with IBD are known to have dysfunctional claudin-1, an intestinal epithelial tight junction protein [99,100]. Irregular functions in claudin-1 leads to changes in cell permeability, causing blood capillary extravasation (hemorrhage), macrophage erythrophagocytosis, and the subsequent release of free HbαC exogenously into the interstitial space [1]. Within the interstitial space, HbαC is observed to serve as a biological substrate in the Fenton Reaction, producing hydroxyl radicals, which leads to DNA damage within normal intestinal mucosa and subsequent tumor formation if the damaged DNA is irreparable [8]. This unveiled molecular understanding of chronic inflammation in patients suffering from IBD provides insight into the evolution of CACRC. Inflammation can induce mutagenesis, and the relapsing–remitting nature of this inflammation, coupled with epithelial regeneration, may exert selective pressure, accelerating carcinogenesis [101]. In summary, the sequential molecular pathogenesis of CACRC is due to inflammation, claudin-1 dysfunction, the extravasation of erythrocytes, macrophage erythrophagocytosis, and exogenous HbαC-ROS-DNAD carcinogenesis [13,47]. Within the interstitial space, HbαC acts as a substrate in the Fenton Reaction (Fe²⁺ + H₂O₂ → Fe³⁺ + ·OH + OH^-) [48].

Ex vivo studies demonstrated a pool of free HbαCs (until recently, an unknown tissue by-product) in IBD patient mucosal microenvironments modulated by extravasated microphage erythrophagocytosis [1]. In vitro data show that HbαC induced high levels of ROS production that caused DNAD, which was exacerbated by systemic decreased antioxidant defenses [1,103,104]. The focus is on the fact that if the Fenton Reaction were mitigated via pharmaceutical therapy, then this would reduce ROS and promote DNAD repair and apoptosis, which could prevent the incidence of CACRC [8].

Colonoscopy surveillance serves as the gold standard for prevention, but it has proven relatively inadequate for ascertaining the earliest molecular pathogenic relationship between neoplasia and chronic inflammation (more specifically, Fenton chemistry and its relationship with exogenous/free HbαC, hydroxyl radical (·OH) formation via the Fenton Reaction (Fe²⁺ + H₂O₂ → Fe³⁺ + ·OH + OH⁻), DNA damage (DNAD), and subsequent tumor formation). The Meharry-Vanderbilt alliance focuses on understanding iron chelation therapy for mitigating in vitro Fenton Reactions through a pharmaceutical approach. HbαC removal may be executed and accomplished using chelation therapy with chelating drugs, i.e., deferoxamine (DF), deferiprone (L1), and flavonoids [105,106], to attenuate HbαC toxicity.

Free haptoglobin is removed from plasma in 3.5–5 days. On the other hand, the haptoglobin–hemoglobin (Hp-Hb) complex is removed within 20 min. This known fact stresses the importance of Hb removal in the presence of Hp. Haptoglobin is a tetrameric protein, a polymer built of four monomer units that contains two light (α) and two heavy (β) chains covalently bound to each other via disulfide bridges. There are three Hp phenotypes: Hp1-1, Hp2-1, and Hp2-2. Haptoglobin polymorphism occurs due to variations in the α-chain; the α-1 chain carries 83 amino acids and the α-2 chain accommodates 142 amino acids. The β-chain encompasses 245 amino acids and is not polymorphic. Further research has proven that the ability of Hp to avoid damage inflicted by free radicals is largely phenotype-pendent. Various phenotypes have the same binding affinities, but the removal of Hp from the extravascular space is size-dependent and removal of the Hp1-1:Hb complex occurs more rapidly, while the Hp2-2:Hb complex is the largest and its removal occurs more slowly. Thus, when complexed with Hp2-2, Hb-α stays in the circulation predominantly and causes enormous oxidative stress via Fenton chemistry [8,110]. Additionally, the prevalence of Hp2 is higher in IBD patients, thus contributing to reduced anti-inflammatory effects and an increased risk of CACRC development in this population [7,111].

Deferoxamine (DFO) is a hydrophilic iron-chelating agent that has been shown to inhibit free radical formation [112,113] and polymeric DFO for enhancing iron chelation cancer therapy. However, its hydrophilic properties limit its ability to cross cell membranes and remain effective in vivo. This feature alone requires higher concentrations and longer incubation periods of DFO in order to yield anti-inflammatory effects (inhibiting the Fe-dependent production of hydroxyl radicals) from the agent. Chelation therapy would remove excess exogenous iron from the body and prevent the production of hydroxyl radicals (−111). Further, antioxidants may also play an important role. Administering antioxidants would neutralize the free radicals and block their harmful effects on intestinal cells. Salicylaldehyde isonicotinoyl hydrazone (SIH) is a lipophilic iron-chelating agent that crosses cell membranes more effectively when compared to DFO, thus requiring lower concentrations and incubation periods to produce similar anti-inflammatory effects when compared to DFO.

Flavonoids are free radical scavengers and confer a wide variety of antioxidant and anti-inflammatory activities [115]. Studies have shown that the enteroendocrine system is composed of enteroendocrine cells (EECs) that regulate IBD by monitoring the gut microbiota and controlling the immune response, thus safeguarding the intestines against physical obstacles, as well as modulating gut motility [116]. Flavonoids have an impact on the enteroendocrine system and safeguard it against IBD, which infers that the alleviation of IBD is possibly associated with the regulation of flavonoids in EECs. Presently, over 4000 multifarious flavonoids have been recognized and ascertained in the bright colors of many fruits and vegetables [117,118]. Further, a number of studies have reported the effect of flavonoids on enterohormone secretion; however, there are hardly any studies demonstrating the association between flavonoids, enterohormone secretion, and IBD. The interplay between flavonoids, enterohormones, and IBD is herein illuminated. Furthermore, the conclusion can be drawn that flavonoids may safeguard against IBD by regulating enterohormones, such as glucagon-like peptide 1 (GLP-1), GLP-2, dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), ghrelin, and cholecystokinin (CCK), a possible mechanism of flavonoids protecting/ shielding against IBD [119].

The most likely way to reduce the incidence of oncological transformation related to IBD is via the clearance of excess exogenous HbαC from the interstitial space. However, this method remains limited until the malfunctioning claudin-1 in the extracellular matrix in the epithelial endothelium and connective tissue is resolved to prevent petechial hemorrhage. This would be the most solid preventive measure to circumvent CACRC development.