Apigenin Offers Great Potential As a Cancer Chemopreventive Agent

Apigenin is commonly found in many fruits and vegetables such as parsley, chamomile, celery, and kumquats. In the last few decades, recognition of apigenin as a cancer chemopreventive agent has increased. Several studies have demonstrated that the anticarcinogenic properties of apigenin occur through regulation of cellular response to oxidative stress and DNA damage, suppression of inflammation and angiogenesis, retardation of cell proliferation, and induction of autophagy and apoptosis.

One of the most well-recognized mechanisms of apigenin is the capability to promote cell cycle arrest and induction of apoptosis. A further role of apigenin in chemoprevention is the induction of autophagy in several human cancer cell lines.

INTRODUCTION

According to a recent report, the projected global cancer burden will rise from 14.1 million new cancer cases in 2012 to 20 million new cases by 2025. In the U.S., more than 1.7 million new cancer cases and over 600,000 cancer deaths are predicted in 2018.

A large body of evidence clearly indicates that primary prevention of cancer is an effective way to fight cancer, with between one-third and one-half of cancers being preventable.

Cancer chemoprevention involves the chronic administration of a synthetic, natural, or biological agents, as either an individual drug or dietary supplement, to reduce or delay the occurrence of malignancies.

At the molecular level, cancer chemoprevention is categorized by the disruption of multiple pathways and processes of the three stages of carcinogenesis: initiation, promotion, and progression. Agents that inhibit the initiation stage are termed “blocking agents” because they may act by preventing interactions between mutagenic substance with DNA, which results in mutations that contribute to not only cancer initiation but also to progressive genomic instability and neoplastic transformation. Agents that inhibit promotion and progression are often referred as “suppressing agents” for their ability to perturb the effects of tumor promoters. In recent years, cancer chemoprevention has emerged as a major approach for the reduction of cancer risk.

Phytochemicals are non-nutritive plant chemicals with protective or disease preventive properties. Phytochemicals are one of typical chemopreventive agents as mentioned above, and exist in abundance in fruits and vegetables. The current consensus is that, in general, cancer risk is inversely associated with the consumption of fruits and vegetables. Polyphenols present in plant-based foods, such as fruits and vegetables, are the most extensively studied group of phytochemicals. Flavonoids are a large subgroup of polyphenols that are present in a wide range of fruits, vegetables, and grains. Previous case-control studies have shown that intake of total flavonoids, flavonoid subgroups, or individual flavonoids was associated with a reduced risk of lung, gastric, colorectal, breast, ovarian, and endometrial cancers and non-Hodgkin’s lymphoma.

NATURAL SOURCES OF APIGENIN

Flavonoids (or bioflavonoids) are a class of plant and fungus secondary metabolites. The compound 4′,5,7-trihydroxyflavone is a natural flavone commonly referred to as apigenin. The name “apigenin”, like many other flavonoids, is derived from Apium genus in Apiaceae (celery, carrot or parsley family, also known as Umbelliferae).

Structure and natural sources of apigenin. Data from US Department of Agriculture (2011; https://www.ars.usda.gov/ARSUserFiles/80400525/Data/Flav/Flav_R03.pdf).

Apigenin is regarded as one of the major flavonoids because of its presence and abundance in a variety of natural sources, including fruits and vegetables. Major sources of apigenin include parsley, chamomile, celery, vinespinach, artichokes, and oregano. Among these, dried parsley is the richest source of apigenin, containing 45,035 μg/g. Other sources of high apigenin content are chamomile (dried flower), celery seed, vinespinach, and Chinese celery, containing 3,000–5,000 μg/g, 786.5 μg/g, 622 μg/g, and 240.2 μg/g, respectively.

ROLE OF APIGENIN IN CANCER PREVENTION

In the 1980s, Birt et al. first demonstrated the effective anti-mutagenic and anti-promotive properties of apigenin. Since then, the potential value of apigenin in cancer prevention and treatment has been further supported by extensive research in various animal models of cancer. For example, research has shown that apigenin can effectively suppress prostate cancer progression, protect against oral carcinogenesis, colon cancer, and UVB-induced skin inflammation in mice. 

ROLE OF APIGENIN IN APOPTOSIS

Apoptosis, or type I PCD (programmed cell death), is one of the most well-characterized types of cell death. Apoptosis is important in cancer biology because PCD is a critical process by which abundant or undesirable cells can be removed. A huge body of evidence demonstrates that deregulation or mutation of apoptosis contributes to the development of numerous pathological conditions, including neurodegenerative diseases, autoimmunity, and cancer. 

The effects of apigenin on apoptosis have been studied extensively in cell populations of many different cancers. Apigenin has been shown either to directly induce apoptosis or to sensitize cells to other pro-apoptotic stimuli in cancer cell lines of oral, esophageal, colorectal, hepatic, and pancreatic cancers. Recent work in pancreatic carcinoma has indicated the possibility that apigenin was capable to promote cell cycle arrest and induction of apoptosis.

ROLE OF APIGENIN IN AUTOPHAGY

The term “autophagy” (“self-eating”) was coined by De Duve and Wattiaux, who discovered a process in which the cell digested its own cytoplasmic materials within lysosomes. Nowadays, autophagy is defined as a catabolic membrane-trafficking process that leads to sequestration and degradation of macromolecules within lysosomes. 

There is growing evidence that the relationship between autophagy and cancer is complex. Initial studies demonstrated that autophagy could impede early cancer development; however, high levels of autophagy in multiple cancers indicated that autophagy primarily promoted the progression of established cancers. Current research indicates that in cancer, autophagy can be neutral, tumor-suppressive, or tumor-promoting under different circumstances.

Due to the contrasting context-dependent roles in tumor progression as discussed previously, a growing body of evidence implicates the biphasic role of autophagy following cancer therapeutics, whereby their anticancer potential may be enhanced or diminished. Conventional cancer therapies (e.g., cytotoxic drug and irradiation) have been shown to induce autophagy. Other anticancer drugs, like targeted therapy drugs (e.g., imatinib, cetuximab, bortezomib, vorinostat) and agents with different mechanisms of action (e.g., tamoxifen, ABT-737, nelfinavir), have also been shown to induce autophagy in tumor cells. Autophagy is stimulated as a protective mechanism to mediate the acquired resistance phenotype of some cancer cells against chemotherapy. In contrast, autophagy may act as an executioner by inducing autophagic cell death, a form of physiological non-apoptotic cell death.

Only a small number of studies have observed the induction of autophagy in response to apigenin. Some research found that apigenin exhibited autophagy-inducing effects in certain types of leukemia, breast cancer, and colon cancer cells.

CONCLUSIONS

Here, we have discussed the beneficial roles of apigenin in the prevention and treatment of cancer through the induction of apoptosis and autophagy. Evidence from both in vitro and in vivo studies suggests that apigenin can trigger apoptosis and/or autophagy, which play pivotal roles in promotion and suppression of carcinogenesis. However, further in-depth investigations are needed to completely understand the mechanism of action and chemopreventive/therapeutic potential against human cancers. The body of evidence concerning apigenin is fascinating and deserves greater attention. As chemoprevention aims to stop the carcinogenic process or to prolong the onset of carcinogenesis by intervention with efficacious, non-toxic, and inexpensive agents to prevent, suppress, or reverse the malignant transformation, apigenin is one such agent that may satisfy most of these requirements. However, further information is required before apigenin can be brought to clinical trials, including data concerning the bioavailability and safety profile in human. Overall, current findings suggest that apigenin offers great potential for further investigation and development as a cancer chemopreventive and/or therapeutic agent.

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