Does Oral Apigenin Have Real Potential for a Therapeutic Effect in the Context of Human Gastrointestinal and Other Cancers?

Abstract

Apigenin (4', 5, 7-trihydroxyflavone) is a plant flavone that has been found to have various actions against cancer cells. We evaluated available evidence to determine whether it is feasible for apigenin to have such effects in human patients. Apigenin taken orally is systemically absorbed and recirculated by enterohepatic and local intestinal pathways. Its bioavailability is in the region of 30%. Once absorbed from the oral route it reaches maximal circulating concentration (C_max) after a time (T_max) of 0.5-2.5h, with an elimination half-life (T¹/₂) averaging 2.52 ± 0.56h. Using a circulating concentration for efficacy of 1-5μmol/L as the target, we evaluated data from both human and rodent pharmacokinetic studies to determine if a therapeutic concentration would be feasible. We find that oral intake of dietary materials would require heroic ingestion amounts and is not feasible. However, use of supplements of semi-purified apigenin in capsule form could reach target blood levels using amounts that are within the range currently acceptable for other supplements and medications. Modified formulations or parenteral injection are suitable but may not be necessary. Further work with direct studies of pharmacokinetics and clinical outcomes are necessary to fully evaluate whether apigenin will contribute to a useful clinical strategy, but given emerging evidence that it may interact beneficially with chemotherapeutic drugs, this is worthy of emphasis. In addition, more effective access to intestinal tissues from the oral route raises the possibility that apigenin may be of particular relevance to gastrointestinal disorders including colorectal cancer.

Keywords: apigenin; cancer; colorectal carcinoma; dietary contituents; natural health products (NHPs); pharmacodynamics; pharmacokinetics; therapeutics.

FIGURE 1

Apigenin and related chemical structures. (A) General flavonoid structure as 15-carbon molecules containing two phenyl groups and a heterocyclic carbon ring. (B) The flavone sub-class of flavonoids have a C2-C3 double bond, unsubstituted C3 carbon, and a C4 ketone oxidization. (C) Apigenin is a 4′, 5, 7-trihydroxyflavone. (D, E) In nature, apigenin is commonly found as a 7-O-glucoside, 6-C-glucoside or 8-C-glucoside, which is enzymatically metabolized to free apigenin prior to intestinal absorption. F) Apigenin undergoes phase I metabolism via CYP1A2, and to a lesser extent CYP3A4, generating the 3′-hydroxylated product luteolin.

FIGURE 2

The absorption, distribution, metabolism, and elimination of apigenin. Apigenin is present in the diet in glycosylated forms found in nature (e.g., 7-O-glucoside, 6-C-glucoside or 8-C-glucoside). These glycosides are then metabolized by β-glucosidases in the stomach and small intestines to generate free apigenin (i.e., the aglycone form). Free apigenin can be directly absorbed systemically, or undergo downstream phase I and II metabolism in the small intestines and liver to generate hydroxylated metabolites such as luteolin, or glucuronidated and sulfonated metabolites. These metabolites enter four possible pathways: i) direct systemic absorption, ii) elimination (mostly via the urine, to a lesser extent the feces), iii) local enteric recycling, or iv) enterohepatic recycling via the bile. Denotes that molecules are subject to recycling through enteric and/or enterohepatic routes. Image adapted from (Thilakarathna and Rupasinghe, 2013).

FIGURE 3

The network of connections between regulatory pathways and molecules that are known to be impacted by apigenin. The functional protein association tool STRING was used to map the inter-connectedness of impacted proteins, identified through physical protein interactions in Homo sapiens, as shown. Connections between nodes are color coded depending on the interaction type: blue, curated databases; fuchsia, experimentally determined; green, textmining; light purple, protein homology. Connections within this network for DPP4, ADA, CSNK2A1, and CDF15 are not shown, but published data on non-physical interactions (e.g., gene co-expression) indicate that such links exist.

FIGURE 4

Apigenin influences on cancer processes. A summary of how apigenin is a key regulator in a number of linked cellular pathways, inhibiting pro-cancerous activity or promoting anti-cancerous activity, yielding a potential overall anti-cancer effect.