Antiproliferative and cytostatic effects of the natural product eupatorin on MDA-MB-468 human breast cancer cells due to CYP1-mediated metabolism

Abstract

Introduction The natural product eupatorin has been reported to have antiproliferative activity in tumour cell lines, but the exact mechanism is unclear. The cytochromes P450 CYP1B1, CYP1A1, and CYP1A2 have been shown to participate in the activation of various xenobiotics, compounds derived from the diet as well as chemotherapeutic drugs. CYP1B1 and CYP1A1 have also been proposed as targets for cancer chemotherapy for their differential and selective overexpression in tumour cells. In this study, we aimed to identify a possible mechanism of action for the antiproliferative effect of eupatorin, which can be attributed to CYP1 family-mediated metabolism.

Antagonism of Aryl Hydrocarbon Receptor Signaling by 6,2′,4′-Trimethoxyflavone

“…Such an observation may be attributable to metabolism of TMF yielding weak agonist potential, as has been described with other flavone derivatives (Androutsopoulos et al, 2008). Nonetheless, TMF seems to have a better antagonist profile compared with described previously compounds and may suggest that improved TMF-derivatives more resistant to metabolism could be developed.…”

Comparative CYP1A1 and CYP1B1 substrate and inhibitor profile of dietary flavonoids

“…16 The latter enzymes promote demethylation reactions at various positions of the polyphenolic moiety, notably the 4 0 -position of the B ring, which gives rise to metabolites with increased pharmacological and antiproliferative activity. [17][18][19] It has been postulated that dietary flavonoids exhibit cancer therapeutic effects, due to intracellular CYP1-mediated metabolism to conversion products that inhibit growth of cancerous cells. [16][17][18][19][20] Thus the duality of flavonoids in cancer therapy and prevention is determined by both, their substrate and inhibitor propensities towards CYP1A1 and CYP1B1 enzymes.…”

“…[17][18][19] It has been postulated that dietary flavonoids exhibit cancer therapeutic effects, due to intracellular CYP1-mediated metabolism to conversion products that inhibit growth of cancerous cells. [16][17][18][19][20] Thus the duality of flavonoids in cancer therapy and prevention is determined by both, their substrate and inhibitor propensities towards CYP1A1 and CYP1B1 enzymes. 16 Inhibition of 7-ethoxyresorufin-O-deethylase activity (EROD) is a well documented assay used predominantly to test the inhibitory potencies of dietary flavonoids.…”

Anticancer effects of the flavonoid diosmetin on cell cycle progression and proliferation of MDA-MB 468 breast cancer cells due to CYP1 activation

“…A more detailed investigation of their versatile activity in cancer prevention has recently revealed a novel mechanism of action in cancer cell line models. Flavonoids such as eupatorin, daidzein and the stilbene resveratrol have been shown to be further activated to cytostatic and cytotoxic agents by the cytochrome P450 enzymes CYP1A1 and CYP1B1 (4)(5)(6). The differential expression of CYP1 enzymes in cancer cells has been proposed before as a target for cancer therapy (7).…”