The dietary flavonoid apigenin enhances the activities of the anti-metastatic protein CD26 on human colon carcinoma cells

Abstract

There is accumulating evidence that secondary plant metabolites such as flavonoids may have anti-cancer properties, and yet the molecular pathways that lead to alterations in cancer cell behaviour remain unclear. We investigated the possible actions of apigenin, a flavone present in leafy vegetables like parsley, on the levels of CD26 in carcinoma cells. CD26 is a multifunctional cell-surface protein that through its associated dipeptidyl peptidase (DPPIV) and ecto-adenosine deaminase (eADA) enzyme activities is able to suppress pathways involved in tumour metastasis. CD26 is down-regulated in various cancers including colorectal carcinoma. Apigenin substantially up-regulated cell-surface CD26 on HT-29 and HRT-18 human colorectal cancer cells. Levels of CD26 protein, along with its associated DPPIV enzyme activity, capacity to bind eADA, and ability to link cells to fibronectin, were increased with a maximum after 24-48 h. Elevation of CD26 occurred at concentrations that were at least 10-fold less than those shown to affect cell growth, and 100-fold below those that could affect cell viability. Furthermore, the CD26 effect was enhanced when apigenin was paired with chemotherapeutic agents utilized in the treatment of advanced colorectal cancer including irinotecan, 5-fluorouracil and oxaliplatin. For irinotecan, apigenin caused a 4-fold increase in the potency of the drug. These results demonstrate that apigenin can increase the cellular levels of CD26 and its multiple functions, and may oppose the predicted effect of decreased DPPIV and eADA activities on carcinoma cells, which is to facilitate tumour growth and metastasis.

Plant Flavone Apigenin: an Emerging Anticancer Agent

“…CD26/DPPIV is down-regulated in various cancers including colorectal carcinoma. Apigenin substantially upregulates CD26/DPPIV on human colorectal cancer HT-29 and HRT-18 cells to inhibit metastasis [81]. Synergistic interaction between apigenin and ABT-263, a BH3 mimetic inhibitor of the Bcl-2 family, was more potent than apigenin or ABT-263 alone in inhibiting tumor growth in xenograft tumors of colon cancer cells [82].…”

Insights into novel anticancer applications for apigenin

“…Research has shown that a reduction of MAPK leads to the inhibition of cell proliferation in human prostate cancer and apoptosis in anaplastic thyroid cancer. 36 Apigenin can also lower the concentrations of the enzymes aromatase and 17b-hydroxysteroid dehydrogenase. Breast and prostate cancer growth is inhibited by the influence of apigenin on estrogen receptor b-1.…”

“…36 It plays an important role in hematological cancer where cell differentiation is inhibited at a particular stage in its maturation. Flavonoid apigenin-7-glucoside can induce acute myeloid leukemia HL-60 cells and chronic myeloid leukemia K562 cells to differentiate the granulocytic and the erythrocytic lineages, which is possible because apigenin increases the expression of alfa and gamma hemoglobin genes.…”

An insight into the role of citrus bioactives in modulation of colon cancer

“…The antitumour actions of apigenin are manifested through modulation of wide range of signalling molecules and their pathways. These include (a) inhibition of mTOR C2 (mammalian target of rapamycin complex-2) via downregulation of RICTOR expression (Guo, Zhou, Evers, & Wang, 2011), (b) decrease in mTOR and cyclin D1 expression (Turktekin et al, 2011), (c) increase in CD26 (cell surface protein), ecto-adenosine deaminase (ADA) binding (Lefort & Blay, 2011), (d) phosphorylation and upregulation of FADD (Fas associated protein with death domain) and expressions of cyclin D1, BAG-1, Bcl-2, yrd-C by acting on PKC δ (protein kinase C) and ataxia-telangiectasia mutated (ATM) kinases pathway (Zhong et al, 2010).…”