Abstract

Chemotherapy works by halting or decreasing the growth of cancer cells, which multiply rapidly. Apigenin can be used to treat cancer, reduce the likelihood of cancer recurrence, stop or delay tumor growth, or shrink tumors that are causing pain and other issues. Although chemical medications are effective, they have a variety of negative effects due to killing or delaying the growth of healthy cells that grow and divide quickly. Thus anticancer therapies based on natural ingredients are emerging. Among these natural ingredients, Apigenin (Api) is a flavonoid that has little toxicity with numerous bioactive qualities. Apigenin has several mechanisms to elicit its actions. Cell cycle arrest, anti-inflammatory, apoptosis, antioxidant activity, anti-carcinogenic, anti-mutagenic, anti-progression and anti-proliferative effects are all examples of Apigenin’s actions. Apigenin is involved in the regulation of several proteins and factors such as Bcl-xL, Bcl-2, TNF-α, HIF-1alpha, VEGF, etc., modulation of different cellular pathways such as TRAIL, PI3K/Akt/Mtor, JAK/ STAT, Wnt/β Catenin & MAPK and regulation of signal transduction. Apigenin is effective in treating and preventing various prevailing cancers including, Breast, cervical, ovarian, colon, oral, prostate, lung, liver, leukemia, lymphoma, melanoma, etc. Apigenin can be used synergistically with cisplatin, 5-fluorouracil, Taxol (Paclitaxel), IFN-gamma, Bcl-2 inhibitors (ABT-263 & HA14-1), Doxorubicin, Chyrophanol and several nano-formulations. Apigenin is also involved in the inhibition of cyclin A, cyclin B & cyclin-dependent kinase-1 [CDK1] expression and Decrease in AKT, P70RSK, and S6 Phosphorylation whereas increasing ERK1/2 and P90RSK phosphorylation.

Keywords: Apigenin, 4’-5-7-trihydroxy-flavone, flavonoids, anti-cancer therapy, mechanism of action, pharmacokinetics, combination therapies.

INTRODUCTION

Cancer is the most prevalent cause of mortality around the world [1, 2]. It is contributing to around 7.6 million deaths globally, with a projected increase to 13.1 million by 2030. Despite innovations in cancer treatment, currently employed treatment modules remain useless due to detrimental effects, therefore efficient cancer therapy has to be made available [2]. Chemotherapy is still one of the most effective cancer treatments available today. With increased application and understanding, the adverse outcomes & developed drug resistance of synthesized small molecular drugs have become increasingly concerning [3]. Combination therapy holds possibilities for improving cancer treatment efficacy and dealing with numerous genetic changes in various cancer cells [4].

APIGENIN AND ITS STRUCTURE

Flavonoids are a type of polyphenolic substance that is abundant in vegetables, fruits, cereals, tea, seeds, and nuts. Many studies have found that flavonoids protect against cancers, cardiovascular diseases [CVDs], and age-related or senile disorders [1]. Among over 6000 different flavonoids, quercetin, kaempferol, myricetin, apigenin, and luteolin are the five most ubiquitous plant

flavonoids [5, 6]. Based on the backbone’s chemical structure, apigenin, also known as 4’,5,7-trihydroxy- flavone, is a flavone (Fig. 1), one of the subclasses of flavonoids. Apigenin has attracted the interest of researchers due to its comparatively low levels of toxicity and numerous positive bioactivities [5]. Apigenin has long been used as a traditional medicine due to its natural antioxidant and anti-inflammatory properties, capacity to decrease blood pressure, and antiviral and antibacterial properties [1]. Apigenin’s antioxidant effects are widely known due to which, it can also be used for therapeutic purposes in disorders such as inflammation, autoimmune disease, neurological disease, and even multiple types of cancer. Principally, glycosylated Apigenin is present in significant amount

in fruits (oranges), vegetables (onions, celery, parsley), herbs (thyme, chamomile, basil, oregano), and plant- based beverages (beer, tea and wine) [7]. Flavonoids like quercetin, apigenin and luteolin were discovered to be the most abundant phenolic ingredients in Rhus coriaria fruits [2]. Since they frequently feature 1 or >1 hydroxyl substituents in their structure, they can also be categorized as polyphenols in terms of their chemical makeup. They are diphenyl-propanoids with a 15 carbon atoms flavane nucleus [C6-C3-C6]. A genetic byproduct of the phenylpropanoid pathway, apigenin can be produced from either phenylalanine or tyrosine [7].

Mechanism of Action of Apigenin (Api)

Apigenin’s potential therapeutic effects were investigated through a variety of pathways, including apoptosis, cell cycle arrest, antioxidant and anti-inflammatory activity [7]. Apigenin also has anti-mutagenic, anti-carcinogenic, anti-proliferative, and anti-progression actions [5]. According to Ghițu A et al.’s thorough evaluation of Api against the A375 human melanoma cancer cell line, the flavone exhibits an anticancer mechanism under the specified experimental conditions that includes inhibition of angiogenesis, induction of apoptosis, modification of the bioenergetic profile, and inhibition of proliferation [8]. Fig. (2) provides a concise synopsis of the process by which Apigenin causes cell cycle arrest, apoptosis, anti- inflammatory, and anti-oxidative actions.

By modifying the expression of certain CDKs and some other genes, apigenin causes cell cycle arrest at various proliferative stages, such as G1/S-phase or G2/M phase [7].

It is understood that by changing the potential of mitochondrial membrane, apigenin is capable of regulating pathways of apoptosis. Apigenin induces cytochrome C release into the cytoplasm, forms APFA, and activates caspase-3, thus initiating apoptotic cell death. Apigenin affects the expression of the proteins STAT-3, Bax, Bcl-2, and Akt to stimulate apoptotic cell death, specifically in cancerous cells [7]. Another study suggests that, in cell lines of squamous cell carcinoma of the skin, Apigenin causes the activation of the Mitogen- activated Protein Kinase [MAPK] signaling pathway, along with down-regulation of Srx expression, both of which leads to induction of apoptosis. Moreover, a different study’s findings indicated that apigenin was also involved in potentiating 5-fluorouracil-induced apoptosis of HCT116 cells besides increased disruption of cell cycle. Furthermore, Ca2+ concentrations inside the cell and mitochondria were also increased by apigenin along with the increased potential of mitochondrial membrane and release of hazardous reactive oxygen species [ROS], when co-treated with 5-fluorouracil [2].

Due to the TNFα stimulus, there is a massive increase of CCL2 [a chemotactic protein], growth factors such as granulocyte-macrophage colony-stimulating factor [GMCSF], and interleukins [IL-1α as well as IL-6], all prevented by the apigenin therapy [2]. Various anti- inflammatory mechanisms are supported by apigenin, including PI3K/Akt and p38/MAPK, in addition to inhibition of degradation of IκB and also nuclear translocation of nuclear factor-κβ, and decrease in COX-2 functioning. It is well known that in lipopolysaccharide [LPS]-activated mice macrophages, apigenin significantly reduced levels of IL-6, which generally acts as an anti-inflammatory myokine as well as a pro-inflammatory cytokine [7].

Apigenin increases antioxidant enzymes such as Catalase, GSH synthase & superoxide dismutase [SOD] to overcome electrophilic and oxidative stress in the cell. Apigenin also increases the expression of specific genes that encode for phase II enzyme by inhibiting the NADPH oxidase complex and their downstream target genes responsible for inflammation as well as by promoting the nuclear translocation of Nrf-2 [7].

According to research, the interaction of apigenin with signaling molecules occurs in three main mitogen- activated protein kinase [MAPK] pathways to cause the suppression of metastasis and angiogenesis: extracellular-signal-regulated kinase [ERK], c-Jun N-terminal kinases [JNK], and p38 in human cell culture models. Apigenin also suppresses TNF-α [tumor necrosis factor], CD40 [cluster of differentiation 40] and IL-6 production by inhibiting phosphorylation of signal transducers, induced by interferon-gamma [IFN-γ], and transcription-1 [STAT1] activators in murine microglia [7].

Effects on Tumor Suppressor Gene

In a study, the usefulness of apigenin in treating primary effusion lymphoma [PEL] has been studied. Physiologically, apigenin is known to inhibit STAT3 and activate the protein p53, which is associated with upregulating catalase. According to research, in samples that received apigenin treatment, there has been a reported increase in p53 protein accumulation. Additionally, apigenin has been proven to phosphorylate p53 in a dose-dependent manner [2].

Mechanisms that Leads to Anti-Cancer Effects of

Apigenin

Apigenin controls various molecular pathways such

as angiogenesis, NF- κβ and regulation of genes that

Table 1: Targeted genes and effects of apigenin.

cause tumor suppression. Apigenin initiates the cell cycle, autophagy and apoptosis. Mechanism of cancer treatment is mainly based on modulating gene activity [2], and is briefed in Table 1.

The mechanism of action of apigenin also significantly involves interactions with different signaling pathways [9], as discussed in Table 2.

Table 2: Apigenin-induced modulations of various signaling pathways.

In vitro Trials of Apigenin

In a clinical trial, apigenin suppresses the PI3K/Akt/ mTOR pathway in hepatocellular carcinoma cells, inhibiting cell proliferation and inducing death. This suggests that apigenin may be a viable chemotherapeutic approach for the treatment of liver cancer [23]. Apigenin exhibits promise as an anticancer drug by causing cell growth arrest and apoptosis in a variety of tumor

types, modifying a number of signaling pathways, and inhibiting invasion, according to a different clinical trial conducted by Imran M, et al. The administration of apigenin results in a decrease in the expressions of Akt, PI3K, NF-κB p105/p50, and p-Akt phosphorylation [24]. Through suppression of the STAT1/COX-2/iNOS signaling cascade, apigenin suppresses inflammation and induces apoptosis, suggesting potential as a therapy for multiple myeloma in another in vitro trial [25]. When human dendritic cells (DCs) were stimulated with high concentrations of API, their metabolic activity was significantly reduced during LPS activation. TNF alpha secretion was decreased by almost 60% whereas IL-6 and IL-10 secretion was virtually entirely stopped [8]. Apigenin successfully stopped the growth of cervical cancer cells and tumors in xenograft mice in a study conducted by Chen Y, et al. Additionally, apigenin induced G2/M-phase cell cycle arrest, reduced EMT to inhibit HeLa and C33A cancer cell migration and down-regulated both FAK signaling (FAK, paxillin, and integrin β1) and PI3K/AKT signaling (PI3K, AKT, and mTOR). Apigenin also inactivated or activated several signaling targets, including Bcl-2, Bax, p21cip1, CDK1, CDC25c, cyclin B1, fibronectin, N-cadherin, vimentin, laminin, and E-cadherin. Thus, it was determined that apigenin might function as a chemotherapeutic agent in the management of cervical cancer [26]. Increased phosphorylation of ERK1/2 and JNK1/2 was brought on by apigenin administration; this prolonged activation reduced ELK-1 phosphorylation and c-FOS expression, which in turn inhibited cell survival. When compared to apigenin therapy, the use of kinase inhibitors caused ERK1/2 phosphorylation, albeit at differing levels, and did not lead to cell cycle arrest. Apigenin significantly reduced the expression of cyclin D1 despite the activation of the MAPK pathway. This reduction coincided with the loss of Rb phosphorylation and the prevention of cell cycle progression. The phosphorylation and expression of p38 and PI3K-Akt, two proteins that regulate cyclin D1 protein, also decreased in tandem with the decreased expression of cyclin D1 protein. Remarkably, apigenin significantly decreased the levels of cyclin D1, D2, and E as well as the regulatory partners CDK 2, 4, and 6, which are involved in the G0-G1 phase of the cell cycle [27].

Pharmacokinetics: Absorption, Distribution, Metabolism and Excretion

Due to considerable inter-individual variability as well as the various biological pathways of its effects on human health, it is generally exceedingly challenging to obtain general or unambiguous information regarding its bioavailability and bioactivity [7]. Because apigenin is poorly soluble with low bioavailability, the colon bacteria may come into contact and break Apigenin down into more readily absorbed forms [5]. It’s recommended to administer Apigenin through the diet. A bioactive substance like apigenin goes through several metabolic processes after consumption to exercise its therapeutic effects, and its pharmacokinetic behavior determines

how it is distributed throughout the body and how active it is in the body’s tissues. The metabolism of apigenin is affected in different ways due to the effect of O-glycosylation or C-glycosylation and thus its antioxidant potential and biological advantages are affected. The unaffected absorption of vitexin-2-O- xyloside [VOX], an apigenin-8-C-glucoside, has been documented in a rat model about the bioavailability of apigenin-C-glycosides. The monoglycoside obtained from hydrolysis, as well as apigenin-8-C-glycoside, the reduced and conjugated glucuronide, undergo enterohepatic recirculation. Apigenin is also capable of crossing the blood-brain barrier after being absorbed into the digestive tract and moving through the circulatory system to the brain, where it can use its affinity for the GABA receptor to affect the central nervous system. Due to the significant potential of food-drug interactions, the use of apigenin in patients receiving traditional pharmaceutical therapy should be cautiously considered [7]. An oral active medication cannot have a logP >5 (i.e. the medicine cannot be too lipophilic) by Lipinski’s “Rule of Five” requirements. With a logP of 2.84, apigenin is classified as a lipophilic substance that can pass through the blood-brain barrier and be permeable to drug membranes while maintaining oral activity. There are currently no thorough in vivo investigations on people that examine the pharmacokinetic characteristics of pure apigenin administered orally [28], and a significant amount of trials have been conducted in rats.

The small intestine may absorb between 5 and 10% of the total amount of polyphenols consumed, primarily as monomers and dimers [5, 29]. Before apigenin enters the systemic or hepatic circulation, it undergoes extensive metabolic and conjugative changes in the gastrointestinal tract [5]. In the duodenum and jejunum, apigenin gets transported through saturable passive and active transports mediated by carrier proteins, as well as by passive mechanisms of transport in the ileum and the colon [5, 30]. Because radioactivity first emerged in the blood after 24 hours of a single oral dosage of radioactive apigenin in rat research, it was determined that the compound has a relatively slow rate of absorption. On the other hand, the maximal plasma concentration of apigenin was attained in another study’s rats 3.9 hours after the first oral administration of Chrysanthemum morifolium extract, which contains apigenin, leading to the contradictory conclusion that apigenin has a rapid absorption rate in rats [5].

Apigenin disperses easily throughout the tissues. In a study, the mean value of the systemic clearance, after an IV dose of apigenin at 20 mg/kg, was 6.12 0.79 L/h/kg. In another study done on rats, after a single oral injection of radioactive apigenin, the elimination half-time was long, measuring 91.8 hours. The plasmatic clearance was

1.95 mL/h, and the distribution volume was 259 mL. The

body excreted and urinated around half of the apigenin is ingested [5].

Apigenin may undergo substantial Phase I and Phase II metabolism after being ingested [5, 29]. Free apigenin can be absorbed systemically directly or can be metabolized downstream in phases I and II in the liver and small intestine to produce glucuronidated and sulfonated metabolites and hydroxylated metabolites like luteolin. These metabolites can go through four different routes: i) enteric recycling locally, ii) elimination (usually through the urine, less frequently through the feces), iii) direct systemic absorption, or iv) enterohepatic recycling through the bile [28]. In the liver of a rat, it was found that the apigenin metabolism involves enzymes of Phase I in the presence of factors such as Cyt-P450 [cytochrome P450 enzymes], nicotinamide adenine dinucleotide phosphate [NADPH], or Flavin-containing monooxygenase [FMO]. In Phase II, both enteric and enterohepatic cycling are involved. The conjugation reactions which are glucuronidation and sulfation, are vital Phase-II pathways of the metabolism of this flavonoid. According to reports, apigenin produces significant amounts of glucuronidated and sulfated conjugate metabolites in both rats and humans. Lutein is the primary hepatic metabolite of apigenin. In human Hep G2 [hepatic cell line], plus Caco-2 [intestinal cell line], apigenin-initiates UDP-glucuronosyltransferase [UGT1A1], a phase II detoxifying enzyme. Intestinal disposition possesses more significance than the hepatic disposition in apigenin’s first-pass metabolism because glucuronidation processes also take place there [5]. Lutein and conjugates of sulfated and glucuronic acids are the main metabolic metabolites of apigenin during metabolism [31], Furthermore, there is proof that these metabolites are active since absorbed apigenin takes the form of luteolin, glucuronide, or sulfate conjugates in tissues and blood circulation [5].

A good sign is the excretion of apigenin following oral consumption through feces since the ingested apigenin is accessible to be metabolized by the intestinal bacteria [5]. Apigenin has a sluggish metabolic and elimination phase, according to a study. Thus, this flavonoid may build up inside the body [32].

Doses, Sources and Routes of Administration of Apigenin

The apigenin dosages that were evaluated in rats were

13.5 and 60 mg/kg. Rat gastrointestinal physiology is difficult to compare to human physiology, but in an adult weighing 70 kg, this corresponds to 0.9 and 4.2 g of apigenin, respectively. When compared to the previously described dosage with dietary parsley, this would result in a roughly 50-240-fold decrease in bulk intake; yet, plasma concentrations should reach the bioactive range in humans (i.e. at least 5μmol/L) through simple extrapolation. Rats given the larger oral dosage during

measurements had a maximum plasma concentration of 1330 ng/ml. Apigenin has a molecular mass of 270g/ mol, which is equivalent to 4.9μmol/L. The rat model and extrapolation from human data so imply that doses employed and approved in experimentation reach systemic levels into the range to generate biological effects, however, this is an approximation based upon limited evidence. In fact, it should be mentioned that mice have been exposed to far larger doses of apigenin—up to 300 mg/kg—without experiencing any overt toxicity or changes in body weight after 68 days. With a 4.2g dose that is greater and an apigenin density of around 1.5g/ml, the resulting product volume would be 2.8 ml. The biggest regularly used capsules have a capacity of 1.37 milliliters. Therefore, to administer this oral dosage in humans, 2.8ml of apigenin powder (representing the dose we predict should yield a 5μmol/L plasma concentration of apigenin) would require two big capsules of purified flavone. As shown above, rats have a T1/2 of 2.1-4.2 hours and humans have a persistence of 6-9 hours after oral administration of parsley. Effective levels could be sustained for long enough to have an impact on the cell behaviors covered in this review with moderate dosages multiple times daily [28].

Since whole plant products like parsley cannot be consumed orally to produce therapeutically relevant apigenin concentrations, the oral dosage form required in a therapeutic context must be of an adequately purified form of apigenin itself. As a health supplement, parsley leaf is available in capsule form; two capsules, or 900 mg, is the usual suggested daily intake. Given that dried parsley has an apigenin level of 45 mg/g, this would translate into a daily dosage of about 40 mg of apigenin—less than 1% of what is required for a significant clinical impact on the behavior of cancer cells—while also potentially having other positive health effects. Therefore, crude plant products are inadequate in this situation [28].

While the major source of Apigenin is nature including fruits [oranges], vegetables [onions, celery, parsley], herbs [thyme, chamomile, basil, oregano], and plant- based beverages [beer, tea and wine] [7], In the form of capsules, powders, apigenin-loaded water-in-oil-in- water emulsions, and apigenin nanoparticles, apigenin is widely utilized in studies and clinical trials. These preparations can be derived synthetically (by using liquid antisolvent precipitation (LAP) technique, bead milling, or high-pressure homogenization) or from natural sources (mainly extracts), but insufficient data was discovered to determine which source is most frequently utilized. According to a study, it is unlikely that eating plant materials high in apigenin—like parsley, which has extremely high levels of the compound— will have biologically significant effects on cells via the vascular route at doses below heroic levels [28], making the synthetic and naturally sourced preparations more important in clinical and research uses.

However, purified apigenin (CAS# 520–36–5) is easily accessible for study and might be scaled up for human consumption by following the right procedures. There are numerous vendors worldwide that offer purity levels between 95% and 98%, derived from both synthetic and natural materials (citrus, chamomile). Apigenin obtained from natural sources is purified using chromatographic techniques and produced as a powder or as a recrystallized form. Feasibility would not be compromised by incorporation into capsules at a normal 97% purity level, and no additional excipients (binding agents, lubricants, fillers, colors) would be needed outside of the cellulose or gelatin capsule casing [28].

Although intravenous apigenin administration is not recommended for people due to a lack of clear justification, it is expected to facilitate biologically active concentrations. Apigenin (20 mg/kg) administered intravenously (IV) in rats resulted in a Cmax of 11.0

± 1.7μg/ml, indicating a plasma concentration over 40μmol/L, adequate to elicit an effect in every cell system examined [28].

Apigenin and Combination Therapies

The efficacy of apigenin is significantly enhanced when used in combination with other chemotherapeutic agents, resulting in synergistic effects that improve therapeutic outcomes (Table 3).

Table 3: Synergistic effects of apigenin in combination with various

chemotherapeutic agents.

Preventive and Therapeutic Roles of Apigenin in Cancer

4’,5,7-trihydroxy-flavone (Apigenin) plays a significant role in the inhibition and thus prevention and treatment of various types of cancer, as mentioned in Table 4.

Table 4: Effects of apigenin on various types of cancer.

Possible Clinical Application and Future Perspectives

Apigenin supplements, which contain pure apigenin in pill form, can be used to raise plasma concentrations that are physiologically significant and may have an impact on cellular activity. Therapeutically speaking, the flavonoid structure presents difficulties for the body’s absorption and subsequent metabolism of the bioactive molecule, despite the fact that Apigenin is easily metabolized by the body as a natural product. Apigenin and similar flavones have weak solubility, moderate permeability, and chemical instability as a result of their molecular makeup. This creates a barrier to a successful treatment plan. However, methods to alter and enhance apigenin’s transport and access to the target region are also made easier by the chemical simplicity of apigenin and the availability of modifiable groups. By using prodrugs, glycosylation, absorption enhancers like cyclopentadecalactone, and nanotechnologies, it is possible to overcome the hindrance caused by fundamental physicochemical properties. There is indeed a chance to profit from this little molecule’s special qualities. The flavone structure can be easily modified by the application of medicinal chemistry [28].

It will take targeted research that combines precise measurements of plasma apigenin levels with clinical outcomes during chemotherapy to determine whether the injection of apigenin will have clinically favorable results. Even though apigenin’s oral and parenteral administration in rat models has yielded some useful pharmacokinetic data, very little direct pharmacokinetic assessment has been conducted in humans, and what has been done is limited to dosing with dietary natural products like parsley [28]. In additional future research, the role of apigenin in the therapy of cancer must be examined based on clinical trials, and any potential modes of action must be clarified.

CONCLUSION

As a naturally occurring Flavonoid, Apigenin has attracted the interest of researchers due to its low toxicity and numerous positive bioactivities. In addition to its well-known antioxidant effects, Apigenin can be used as a treatment for illnesses like autoimmune diseases, inflammation, neurological diseases, and even various types of cancer including Breast, colon, lung, liver, prostate, brain, oral, skin, cervical, ovarian, pancreatic and esophageal cancers, leukemia, lymphoma and melanomas. Its mechanism of action is mainly based on arrest of the cell division cycle, apoptotic cell death and

anti-oxidant and anti-inflammatory function. Apigenin possesses features that are anti-mutagenic, anti- carcinogenic, anti-proliferative, and anti-progression. Additionally, interactions with other signaling pathways (TRAIL, Wnt/β Catenin, JAK/STAT, PI3K/Akt/mTOR, and MAPK) are crucial to understanding how apigenin works. Given the significant inter-individual variation and the numerous molecular mechanisms by which Apigenin affects human health, it is generally exceedingly challenging to obtain general or unambiguous information regarding its bioavailability and bioactivity. In summary, based on the literature to date, Apigenin has been demonstrated to be useful in combinatorial therapies [especially with cisplatin, 5-fluorouracil, Taxol, Gemcitabine, Gafitinib and Doxorubicin] but still lacks strong scientific evidence.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

ACKNOWLEDGEMENTS

Declared none.

AUTHORS’ CONTRIBUTION

Areeba Khan (write-up – original & final draft preparation, conceptualization & proofreading), Farah Kishwar (supervision, data verification, review & editing the manuscript), Muhammad Talha Khan (Write-up – original draft preparation).

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