Apigenin, also known as 4′,5,7-trihydroxyflavone [1], is a natural chemical from the flavone group found in vegetables and fruits, including olives, onions, celery, oranges, and chamomile [2]. Plants belonging to the Asteraceae botanical family are the principal sources of this compound. It is synthesized in the phenylpropanoid pathway and is obtained from the phenylalanine and tyrosine amino acids [3]. Like other flavonoids, apigenin is known for its antioxidant properties [4]. It presents hypoglycemic [5], anti-inflammatory [6], and cytostatic and cytotoxic properties for various cancer cells [7]. Apigenin also has anti-apoptotic effects in myocardial ischemia [8].
Apigenin's low solubility in water and low bioavailability [9,10] limit its potential biological effects. Different delivery systems, including lysosomes, polymeric micelles, and nanosuspension, can improve its solubility [11-13], and a study in vitro suggests that injectable nanocapsules may be a suitable approach to achieve prolonged apigenin pharmacological activity [14].
In this article, we delve into the therapeutic potential of apigenin, including its mechanism of action, the benefits of apigenin, and current limitations in studies.
Apigenin mechanisms of action
Apigenin exhibits multiple functions in vitro through various mechanisms, highlighting its potential therapeutic applications. For instance, it modulates the expression of different genes, including CDKs, inducing cell cycle arrest at different stages (G1/S or G2/M phases) [15,16]. It regulates intrinsic apoptotic pathways by altering the mitochondrial membrane potential, which leads to the cytoplasmic release of cytochrome C and the activation of caspase-3, ultimately resulting in cell apoptosis [17]. Apigenin also modulates extrinsic apoptosis pathways via caspase-8 activation. In cancer cells, apigenin enhances apoptosis via increasing Bcl-2, Bax, STAT-3, and Akt proteins [18,19]. It demonstrates anti-inflammatory properties by reducing COX-2 activity, promoting the p38/MAPK and PI3K/Akt pathways, and preventing IKB degradation and NF-κB nuclear translocation [20,21]. Additionally, it inhibits the expression of pro-inflammatory cytokines, such as IL-6 [22], by blocking the phosphorylation of the p65 subunit and the subsequent activation of NF-κB [23].
Consequently, apigenin suppresses lipopolysaccharide-induced lethality [23]. Apigenin also presents antioxidant properties. It significantly increases the expression of GSH-synthase, catalase, and SOD, three antioxidant enzymes that counteract oxidative stress, and decreases the levels of lipid peroxidase [24]. It enhances the expression of phase II detoxifying enzyme-encoding genes by inhibiting the NADPH oxidase complex and its downstream target inflammatory genes while promoting the nuclear translocation of Nrf2 [25]. Finally, apigenin modulates signaling molecules in the three principal MAPK pathways: ERK, c-JNK, and p38 in human cells in vitro [26]. These findings underscore the multiplicity of apigenin's mechanisms of action, ranging from gene expression modulation and apoptosis regulation to anti-inflammatory and antioxidant effects, highlighting its diverse therapeutic potential across various cellular pathways.
Apigenin’s anti-diabetic properties
In vitro, apigenin inhibits the human α-amylase. This enzyme controls glucose assimilation, via a competitive mechanism by occupying its binding site [27-30], and the intestinal α-glucosidase, an enzyme involved in the absorption of glucose in the gastrointestinal tract [31-33]. It is a potent and selective inhibitor of the GLUT2 transporter, a protein that accounts for about 60% and 75% of total fructose and glucose uptake from the intestinal lumen, respectively, following a meal [34,35]. It also increases insulin secretion [36]. In high-fat diet-induced obese mice, apigenin treatment reduced glycemia and insulin resistance index and improved glucose tolerance [37]. Therefore, apigenin potentially appears as a good alternative to regulate postprandial carbohydrate absorption, alone or combined with anti-diabetic drugs for an enhanced formulation.
Apigenin’s antitumor properties
Apigenin shows cytostatic and cytotoxic effects on various cancer cells in vitro, including pancreatic cancer [38,39], breast cancer [40,41], ovarian cancer [42], lung cancer [43], and colorectal cancer [44] cell lines. In several experiments (in vitro and in vivo), apigenin showed antitumor properties with a significantly prolonged survival time and suppression of tumor growth [45,46]. This antitumor effect may result from apigenin’s ability to inhibit the activation of IKKα, which in turn does not activate NF-κB, as previously mentioned, and subsequent downregulation of genes involved in proliferation (such as the genes coding for cyclin D1 and COX-2), anti-apoptosis (Bcl-2 and Bcl-xL), and angiogenesis (VEGF)[17,38,39,47,48,48,49]. Therefore, apigenin shows potential as an antitumor substance.
The effects of apigenin on the liver
Apigenin may exert a protective effect on the liver via its antioxidant activity, including the enhanced expression of antioxidant enzymes (GSH-synthase, catalase, and SOD) and decreased levels of lipid peroxidase. After apigenin treatment of hepatoma cells, the expression of Nrf2-mediated antioxidant genes that protect against oxidative damage increases [50], suggesting that apigenin enhances the scavenging of reactive oxygen species. In addition, apigenin reduces hepatic inflammatory cytokines, such as TNF-α, IL-1β, and IL-6. However, apigenin treatment at high doses triggers hepatic damage in mice with oxidative stress and apoptosis [51]. Therefore, further research is required to understand apigenin’s therapeutic potential for liver health.
The effects of apigenin on the cardiovascular system
Apigenin shows protective effects on the cardiovascular system. For instance, it enhances nitric oxide levels in the aorta, thus protecting the vascular endothelium [52]. By inhibiting the angiotensin-converting enzyme, apigenin reduces blood pressure [53]. It decreases atherogenesis via the induction of macrophage apoptosis and the subsequent reduction of inflammatory cytokines (TNF-α, IL-21, and IL-6) [54]. Several studies suggest that it may also protect the heart against ischemia and reperfusion injuries by up-regulating the expression of Bcl-2 and reducing the p38 mitogen-activated protein kinase signaling pathway [55-57]. These findings highlight apigenin's potential as a therapeutic agent to prevent and treat cardiovascular diseases.
Current limitations
Apigenin research has principally focused on in vitro experiments. Studies on animal models, including rats and mice, are limited, and available human data from clinical trials are reduced. Although great efforts have been made to tackle its low bioavailability, its high metabolic transformation, similar to other phytochemicals, remains an unsolved issue to demonstrate this substance’s structure-function relationship [1].
Conclusion
Apigenin exhibits numerous beneficial effects, including hypoglycemic, antioxidant, anti-inflammatory, antitumor, and hypotensive properties. However, most of these observed effects were observed in vitro. Further research, particularly in animal models and human studies, is needed to understand and confirm the therapeutic potential of apigenin.
Research has studied the effect of apigenin on cancer cells, particularly breast cancer cells, and has shown that apigenin induces apoptosis by apigenin in humans and inhibits cancer progression. The flavonoid apigenin has also demonstrated antitumor effects, with studies evaluating the impact of apigenin in patients with resected colorectal cancer to prevent recurrence. Additionally, combining apigenin with other flavonoids like quercetin and apigenin or apigenin and naringenin has been explored for enhanced therapeutic outcomes.
Despite promising findings, further research is needed to fully understand the chemopreventive potential of apigenin and its applications in clinical settings. Future studies should also investigate its dose-dependent hepatotoxicity and thoroughly evaluate its safety profile to ensure clinical applicability.
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