Flavonoids’ Dual Benefits in Gastrointestinal Cancer and Diabetes: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Raghad Khalid AL-Ishaq
,
Alena Mazurakova
,
Peter Kubatka
,
Dietrich Büsselberg

Diabetes and gastrointestinal cancers (GI) are global health conditions with a massive burden on patients’ lives worldwide. The development of both conditions is influenced by several factors, such as diet, genetics, environment, and infection, which shows a potential link between them. Flavonoids are naturally occurring phenolic compounds present in fruits and vegetables. Once ingested, unabsorbed flavonoids reaching the colon undergo enzymatic modification by the gut microbiome to facilitate absorption and produce ring fission products. The metabolized flavonoids exert antidiabetic and anti-GI cancer properties, targeting major impaired pathways such as apoptosis and cellular proliferation in both conditions, suggesting the potentially dual effects of flavonoids on diabetes and GI cancers. This review summarizes the current knowledge on the impact of flavonoids on diabetes and GI cancers in four significant pathways. It also addresses the synergistic effects of selected flavonoids on both conditions. While this is an intriguing approach, more studies are required to better understand the mechanism of how flavonoids can influence the same impaired pathways with different outcomes depending on the disease.

  • flavonoid
  • diabetes
  • GI cancer
  • dual
  • synergetic

Introduction

Diabetes

Diabetes is a chronic and complex metabolic disorder with a high prevalence rate worldwide [1]. It is classified into type 1, type 2, and gestational diabetes. These types differ in their diagnostic criteria, genetics, and etiology [2]. Type 2 and gestational diabetes are attributed to unhealthy diet and lifestyle, aging, and urbanization [3]. Diabetes is categorized by hyperglycemia, a continued elevation of blood glucose levels caused either by a defect in insulin secretion or action [4] due to which multiple organs, such as the eyes, heart, and kidneys, become deleterious, leading to organ damage, dysfunction, and, ultimately, organ failure [5,6]. Additionally, complications of diabetes could have profound adverse effects on the social, psychological, and physical health of patients and their families [7]. Symptoms and signs of diabetes include polyuria, polyphagia, polydipsia, blurred vision, and weight loss. Their severity depends on the type and duration of diabetes [8]. Currently, diabetes is treated by administering oral hypoglycemic drugs, antidiabetic drugs, and lifestyle management [9,10]. Further efforts are needed for the development of new therapeutic agents.

Gastrointestinal Cancer

Gastrointestinal cancer (GI) is one of the major causes of death and disability worldwide [11]. The term “GI cancer” describes cancers that affect the digestive system, including, but not limited to, colorectal cancer and gastric cancer [12]. It is a multifactorial disease and can be influenced by environmental and genetic factors such as obesity, diet, smoking, infection, and low socioeconomic status [13,14]. The symptoms of GI cancers depend on their etiology and may include weight loss, fatigue, anorexia, abdominal pain, and dysphagia [15]. GI cancer progression results from the impairment of major metabolic pathways, such as the intrinsic and extrinsic apoptotic pathways, cellular proliferation pathways, and metastatic pathways [16,17]. The field of cancer treatment is evolving continuously, and the applications of precision medicine and combination therapy provide an alternative approach and result in the long-term survival of patients with GI cancers [18]. Despite this, more efforts are required to estimate GI cancers’ underlying mechanisms and develop new therapeutic approaches for prevention and treatment.

Flavonoids Influence Diabetes and GI Cancer

Flavonoids are secondary metabolites derived mainly from plants, fruits, leaves, and vegetables [19]. They represent a large family of compounds consisting of benzopyran rings with polyphenolic groups at different positions. The structure of flavonoids consists of 15 carbons and two rings (A and B) linked by three carbon chains [20] (Figure 1). Flavonoids are classified into multiple types based on their chemical structure, unsaturated linking chain, and degree of oxidation [21]. Each of these groups possesses biological properties, and some are successfully used in therapeutic approaches for treating diabetes and GI cancer [22]. The administration of flavonoids to target diabetes modulated lipid and carbohydrate metabolisms, improved adipose tissue metabolism, attenuated hyperglycemia, and alleviated oxidative stress [23,24]. Moreover, for targeting GI cancer, flavonoids in berries and green tea reduced cellular proliferation and inflammation, inhibited metastasis, and increased apoptosis [25,26]. Additional efforts are necessary to address the mechanism of flavonoids in treating metabolic disorders such as diabetes and cancer.

Gut Microbiota: The Role in Diabetes and GI Cancer

The human digestive tract harbors several microbial species collectively called the gut microbiome [27]. The human gut microbiome influences health and disease status through its involvement in human nutrition, immunity, and physiology [28]. Recently, we reported the effect of gut microbiome enzymatic modifications on flavonoid metabolism and how these modifications affect the observed biological properties of flavonoids [29].
Human gut microbiome diversity disruption is linked to pathological conditions such as inflammatory bowel disease (IBD), obesity, diabetes, and cancers [30,31]. In two population-based studies, the diversity and richness of the gut microbiome were associated directly with the development of type 2 diabetes and insulin resistance [32]. Furthermore, the gut microbiome’s impact on cancer is not only limited to specific pathways such as apoptosis and cellular proliferation, but also enhances the efficacy and reduces the resistance of chemotherapeutic drugs [33]. Figure 2 and Figure 3 summarize the overall interactions between the gut microbiome and specific pathways during diabetes and GI cancer.

Flavonoids and Apoptosis in Diabetes and GI Cancers

Cellular apoptosis is programmed cell death that involves numerous regulatory genes [36]. These regulatory checkpoints are critical to maintaining a homeostatic balance between the newly formed and damaged cells [37]. Loss of this balance may lead to the development of diseases such as diabetes and/or GI cancers [38]. Flavonoids restore the imbalance in these conditions [39].
In diabetes, long-term hyperglycemia in patients may contribute to the accumulation of reactive oxygen species (ROS), which results in endothelial cellular stress [40]. If unresolved, it may lead to apoptosis of microvascular endothelial cells, which, in turn, results in diabetic complications such as diabetic cardiomyopathy and diabetic nephrosis [41]. However, baicalin, a flavone glycoside in tea, fruits, and vegetables, reduces apoptosis in a rat model of diabetes mellitus, thus supporting the neuroprotective efficacy of baicalein against diabetes-associated cognitive deficits [42]. Moreover, a study that stimulated diabetic mice cells with 60.0 M of glucose to induce oxidative stress showed that cells treated with baicalin had significantly alleviated oxidative stress and apoptosis through the regulation of PERK/Nrf2 pathway [43]. Additionally, hesperidin, a glycosidic flavonoid abundant in citrus fruit, also reduces oxidative stress [44]. Normal human hepatocytes stimulated with 33 mM of glucose for 24 h and then treated with hesperidin had improved oxidative stress levels and increased cell viability compared to the untreated cells. These findings demonstrated that hesperidin treatment might reduce apoptosis by regulating miR- 149 expression, a critical apoptotic regulator [45]. Similarly, rutin also alleviated diabetic complications through apoptosis [46]. Myoplast cells stimulated with different glucose concentrations and then treated with rutin showed an improvement in cardiomyocyte injury through the direct inhibition of apoptosis and endoplasmic reticulum stress [47].
The reduction of apoptotic regulation allows cancerous cells to survive and progress [48]. Flavonoids such as apigenin, a plant flavone, induce cell cycle arrest, disruption, and apoptosis with low toxicity and mutagenicity rates [49]. Additionally, 200 umol/L of genistein for 48 h affected both Notch 1 and epithelial-mesenchymal transition (EMT) pathways and significantly induced apoptosis in colorectal cancer cells [50]. Moreover, the administration of 50 uM of Kaempferol also decreased the Bcl-2 level and increased the cleaved caspase 9 expression, thus inducing apoptosis in gastric cancer cells [51]. Interestingly, the same apoptotic pathway may be targeted by different flavonoid types such as chrysin, morin, and hesperidin. All three flavonoids induced apoptosis separately through the modulation of caspase 3, 9, and BAX expression in colorectal cancer or gastric cancer cells [52,53,54]. Moreover, cotreatment of apigenin and 5-flurouracil increased ROS and mitochondrial membrane potential in colorectal cancer cells, supporting flavonoids’ potential role as a therapeutic agent [55]. Figure 5 summarizes the influence of specific flavonoids on the apoptotic pathways in diabetes and GI cancers.
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Figure 5. Illustrations of the influence of specific flavonoids on apoptotic pathways in diabetes and GI cancers. The figure highlights the pathological changes in apoptosis during both conditions, the flavonoids’ effect, and the mechanisms through which the flavonoids target the pathway. Created with BioRender.com.

Flavonoids and NF-κB Pathway in Diabetes and GI Cancers

Nuclear factor kappa B (NF-κB) transcription factors are critical regulators of the inflammatory and immune responses against infections and injuries [56]. NF-κB dysregulation may lead to the development of cancers, chronic inflammation, and insulin resistance [57]. The activation of NF-κB by oxidative stress in diabetic patients due to the high glucose level plays a crucial role in the vascular complications of diabetes [58]. Additionally, persistent hyperglycemia in diabetes triggers the expression of chemokines, cytokines, and cell adhesion molecules by activating NF-κB expression [59]. Furthermore, activation of the NF-κB pathway correlates with GI cancers’ tumor size, migration, and invasion through the modulation of inflammatory markers, just as in the pathogenesis of GI cancers [60]. Targeting the NF-κB pathway with flavonoids is reported to be a potential therapeutic target for diabetes and GI cancers [61,62].
Different flavonoids exert antidiabetic properties. Baicalin, a bioactive polyphenolic flavonoid, administered to diabetic mice significantly reduced glucose levels and inhibited insulin levels [63]. Additionally, the administered baicalin attenuated steatosis in diabetic mice’s hepatic tissues through the suppression of inflammatory cytokines regulated by the NF-κB pathway. Treatment with 20 mg/kg of apigenin also reduced NF-κB and TNF-a expression and inhibited mouse inflammations [64]. Moreover, luteolin significantly reduced oxidative stress by inhibiting the NF-κB and activating the nuclear factor-erythroid 2-related factor 2 signaling pathway [65]. Interestingly, as reported with quercetin, flavonoids inhibit NF-κB expression and target vascular complications in diabetes [66]. Daily administration of quercetin in rats for six weeks reduced NF-κB expression and protects against diabetic-induced exaggerated vasoconstriction.
Flavonoids also play a significant role in targeting the NF-κB pathway through different mechanisms in gastric cancer (GC). Chrysin, for example, significantly suppressed NF-κB and Egr-1 expression in gastric cancer cells by inhibiting endogenous recepteur d’órigine nantais (RON) expression and activity, a critical receptor for cancer cell invasion [67]. Additionally, treating colorectal cancer cells with morin suppressed the expression of NF-κB and the production of inflammatory cytokines such IL-8 and IL-6 [68]. Furthermore, genistein administration in gastric cells targeted and significantly reduced the expression of Cyclooxygenase-2 (COX-2), an isoenzyme critical in cancer progression, by targeting and inhibiting its regulator, NF-κB [69]. Quercetin also downregulated the NF-κB pathway, influencing the invasion, migration, and metastasis of gastric cancer cells [70]. Figure 6 highlights the influence of specific flavonoids on the NF-κB pathway and expression in diabetes and GI cancers.
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Figure 6. Summary of the influence of specific flavonoids on NF-κB pathways in diabetes and GI cancers. The figure highlights the pathological changes in the pathway with both conditions, the flavonoids’ effect, and the mechanisms through which the flavonoids target the pathway. Created with BioRender.com.

The paper also address the influence of Flavonoids on AMPK Pathway and Enzymatic Activities in Diabetes and GI Cancers. 

Discussion

Targeting Multiple Pathways with Multiple Flavonoids That Act Synergistically?

As mentioned in the previous sections and the figures, the same flavonoid can trigger and improve diabetes and/or cancer-related pathways, as seen with baicalin and genistein, respectively. Baicalin, for example, exerts its antidiabetic effects by targeting three out of four discussed pathways: apoptosis, NF-κB, and enzymatic modification. Genistein, on the other hand, triggers apoptosis, NF-κB, and AMPK pathways in cancer. Therefore, can the positive effects of flavonoids on physiological pathways be further enhanced when different flavonoids are combined to complement and trigger additional pathways? For instance, with baicalin targeting three diabetic-impaired pathways, combining baicalin with one of the flavonoids that target the AMPK pathway in diabetes (Figure 7) might potentially initiate a positive effect in all four of the discussed pathways due to synergistic effects of both phytochemicals. This hypothesized approach may prevent the over-activation of the same pathway and reduce possible side effects while achieving the antidiabetic effects of these flavonoids. The same approach may also be used with genistein in GI cancer. So far, these thoughts are theoretical and only based on observation from the data cited above. In vitro or in vivo studies are still missing, and extensive studies are required to prove whether they are effective in an expected way. This hypothesis may be tested by first identifying the pathways targeted by the flavonoid in each metabolic condition, then identifying flavonoids that complement each other. Furthermore, estimating the appropriate concentration of each flavonoid is critical to ensure safety and prevent cytotoxicity. Recognizing the potential binding sites of each flavonoid and their bioavailability is essential to ensure their positive effects. Moreover, observing possible side effects from this combination with the currently used treatment is necessary, as the aim is not to replace the available therapeutic tools, but to complement them.

Gut Microbiome and Flavonoids’ Effects

The relationship between the gut microbiome and flavonoids may be described as a bidirectional interaction. On the one hand, the consumed flavonoids act as a regulator of intestinal hemostasis by either enhancing or suppressing the growth of specific bacterial species. On the other hand, the gut microbiome contributes to the pharmacokinetics of ingested dietary flavonoids to produce aglycones and, subsequently, the ring fission products which facilitate absorption [108,109,110]. It is hypothesized that these enzymatically modified gut microbiome products are responsible for the positive physiological effects of flavonoids observed in diabetes and GI cancer (Figure 2 and Figure 3). This may provide a potential therapeutic target for both metabolic conditions. Patients with type 2 diabetes exhibit gut microbiome dysbiosis characterized by a reduction in butyrate-producing bacterial species [111]. Additionally, the gut microbiome regulates the levels of short-chain fatty acids and lipopolysaccharides, which are critical for developing diabetes [112]. Furthermore, patients with type 2 diabetes exert a low-grade systemic inflammation mediated by the impaired gut barrier [113].
On the other hand, gut microbial species such as Streptococcus bovis, Fusobacterium nucleatum, and Enterococcus faecalis mediate inflammatory response and tumor progression in colorectal cancer [114,115]. The data above show that flavonoids and their metabolites could reduce or restore the observed pathological effects in diabetes and GI cancers. Despite this, more efforts are required to properly study the gut microbiome, including a suitable model and flavonoid interactions. More studies are required to evaluate whether the positive/dual effects observed are due to the flavonoids, their metabolites, or both. In addition, more efforts are needed to address the metabolites from the gut microbiome and the liver, and especially to discuss and understand the substances metabolized in the liver [116]. The development of more omics tools that help analyze data is necessary [117].

Challenges with Studying the Field

Although flavonoids reduce the pathogenesis of diabetes and GI cancers, further efforts are required to address the main challenges of their utilization in managing cancer and diabetes. First, the recommended dosage of flavonoids for each metabolic condition must be established. The literature shows variations in the estimated dosage for most flavonoids tested based on the population, ethnicity, gender, and geographical locations [118,119,120]. The observed variations may be due to the solubility and molecular weight of the flavonoids used [121]. Second, newly developed tools and techniques are required to overcome flavonoids’ relatively low bioavailability rate.
Additionally, a better understanding of flavonoids’ cellular permeability, excretion, and metabolic alternation is needed to enhance their bioavailability [122]. Third, the potential side effects of using multiple flavonoids to target various metabolic pathways or using flavonoids in combination with currently used drugs as a treatment method must be estimated. This will help to minimize the risk of negative flavonoid–drug interactions. Fourth, the field is in great need of standardization starting from the model used, flavonoid extraction and purification technique, administration route, and duration of the treatment. By overcoming these challenges, using flavonoids as a potential therapeutic target may be implemented with high effectiveness and safety levels.

GI Cancers and Diabetes: Their Relationship?

The prevalence of diabetes mellitus among patients with GI cancers varies depending on the tumor type. For example, the highest rate of diabetes mellitus was seen in patients with colon cancer (15.5%), rectal cancer (15.3%), and stomach cancer (14%) [123]. On the other hand, diabetes in patients can promote the progression, development, and metastasis of gastric cancers [124]. The observed association may be due to the shared risk factors between both conditions such as diet, smoking, infection, medication, obesity, and hyperglycemia [125]. More data are still needed to identify which condition comes first and whether we can predict the occurrence of one following the other. Despite this, the available data suggest a possible association between both conditions and how they may be targeted using flavonoids as a novel therapeutic agent, which might help improve the quality of the patients’ lives and reduce the burden of both conditions.

Conclusions

Flavonoids are naturally occurring products found abundantly in fruits and vegetables. Upon ingestion, flavonoids are further metabolized by the gut microbiome into aglycones that exert antidiabetic and anti-GI cancer effects. Based on the current evidence, flavonoids target impaired pathways such as apoptosis and NF-κB in both conditions [126,127]. Despite this, the mechanisms by which flavonoids target the same pathway with different biological effects depending on the metabolic conditions need further research. Only limited evidence from the literature supports a potential dual effect of flavonoids.
Moreover, a combination of several flavonoids (affecting the pathology synergistically or additively) represents a promising strategy to be further evaluated to target impaired pathways. Still, more efforts are required for protocol standardization to ensure safety and effectiveness. Similarly, vitexin, an apigenin flavone glucoside, exerts beneficial effects in high glucose-induced endothelial cells via inhibition of apoptosis and oxidative stress, thus suggesting the potential effectiveness of vitexin in cardiovascular complications of diabetes. Specifically, vitexin decreased apoptosis via the disruption of Wnt/β-catenin and Nrf2, decreased ROS and malondialdehyde content, and increased superoxide dismutase activity in HG-mediated HUVECs [128]. In addition to isolated flavonoid compounds, extracts rich in flavonoids were also reported to influence metabolic pathways, such as Oldenlandia diffusa, which induced apoptosis via ROS accumulation, mitochondrial membrane potential loss, and activation of mitochondrial pathway in gastric cancer in vitro and in vivo [129]. In this regard, a lack of understanding of flavonoids’ complex mechanisms of action, non-specific selectivity, and low bioavailability in organisms markedly impedes their pharmacological administration in clinical practice. Mentioned obstacles could be overcome using progressive methodological approaches in medicine, i.e., designing nano-engineering systems to achieve the delivery of flavonoids into targeted organs and tissues. Such techniques could improve flavonoids’ efficacy and pharmacokinetic properties in diabetic cancer patients.
Our paper provides a theoretical base for advancing highly effective and low-toxicity flavonoid-based pharmaceutical molecules or their mixtures to target complex signaling pathways associated with diabetes and cancer concurrently. However, only precisely designed and well-controlled clinical evaluations of the context of the antidiabetic and anti-cancer effects of bioactive flavonoids could establish the role of these polyphenolic compounds as beneficial agents in diabetic and GI cancer patients.
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This entry is adapted from the peer-reviewed paper 10.3390/cancers14246073

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