Anti-Neoplastic Activity of Two Flavone Isomers Derived from Gnaphalium elegans and Achyrocline bogotensis

Abstract

Over 4000 flavonoids have been identified so far and among these, many are known to have antitumor activities. The basis of the relationships between chemical structures, type and position of substituent groups and the effects these compounds exert specifically on cancer cells are not completely elucidated. Here we report the differential cytotoxic effects of two flavone isomers on human cancer cells from breast (MCF7, SK-BR-3), colon (Caco-2, HCT116), pancreas (MIA PaCa, Panc 28), and prostate (PC3, LNCaP) that vary in differentiation status and tumorigenic potential. These flavones are derived from plants of the family Asteraceae , genera Gnaphalium and Achyrocline reputed to have anti-cancer properties. Our studies indicate that 5,7-dihydroxy-3,6,8-trimethoxy-2-phenyl-4H-chromen-4-one (5,7-dihydroxy-3,6,8-trimethoxy flavone) displays potent activity against more differentiated carcinomas of the colon (Caco-2), and pancreas (Panc28), whereas 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3,5-dihydroxy-6,7,8-trimethoxy flavone) cytototoxic action is observed on poorly differentiated carcinomas of the colon (HCT116), pancreas (Mia PaCa), and breast (SK-BR3). Both flavones induced cell death (>50%) as proven by MTT cell viability assay in these cancer cell lines, all of which are regarded as highly tumorigenic. At the concentrations studied (5–80 µM), neither flavone demonstrated activity against the less tumorigenic cell lines, breast cancer MCF-7 cells, androgen-responsive LNCaP human prostate cancer line, and androgen-unresponsive PC3 prostate cancer cells. 5,7-dihydroxy-3,6,8-trimethoxy-2-phenyl-4H-chromen-4-one (5,7-dihydroxy-3,6,8-trimethoxy flavone) displays activity against more differentiated carcinomas of the colon and pancreas, but minimal cytotoxicity on poorly differentiated carcinomas of these organs. On the contrary, 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3,5-dihydroxy-6,7,8-trimethoxy flavone) is highly cytotoxic to poorly differentiated carcinomas of the colon, pancreas, and breast with minimal activity against more differentiated carcinomas of the same organs. These differential effects suggest activation of distinct apoptotic pathways. In conclusion, the specific chemical properties of these two flavone isomers dictate mechanistic properties which may be relevant when evaluating biological responses to flavones.

Free-B-Ring flavonoids as potential lead compounds for colon cancer therapy

“…That initial study was further supported by the observation that flavone increased early and late apoptosis parameters in Caco-2 cells (21). Additionally, those findings were reinforced by more recent studies, demonstrating that 5,7-dihydroxy-3,6,8-trimethoxy flavone displayed a potent activity against the more differentiated carcinomas of the colon compared to its flavonol isomer, 5-hydroxy-6,7,8-trimethoxy-3-flavonol (22). Taken together, those findings have formed the concept of Free-B-Ring flavonoids as potential anticolon cancer agents and several mechanisms have been proposed regarding their anticancer activity.…”

ALPHA ANTIADRENERGIC EFFECT OF Achyrocline bogotensis EXTRACT (“Vira Vira”) IN ISOLATED RAT AORTIC RING

“…Previous works have led to the isolation of 3,5-dihydroxy-6,7,8-trimethoxy flavone from A. bogotensis, a compound that possess in vitro antineoplasic activity against several tumorigenic cell lines (9,12,28). This flavone could also play a pivotal role in the smooth muscle relaxant effects of A. bogotensis.…”

“…tory actions (9)(10)(11)(12). Achyrocline species subjected to chemical and biological studies include A. satureioides (13)(14)(15)(16), A. alata (17)(18)(19), A. tomentosa, (20,21) and A. flaccida (22,23).…”

Quantification of two isomeric flavones in rat colon tissue using reverse phase high performance liquid chromatography

“…It is known that these activities are greatly determined by their chemical structure which subsequently dictates their ability to interact with cellular molecules [1]. This differential effect has been observed with flavone isomers 5,7-dihydroxy-3,6,8-trimethoxy flavone (flavone A) and 3,5-dihydroxy-6,7,8-trimethoxy flavone (flavone B) [5]. Specifically, each isomer has been shown to target colon cancer cells with distinct phenotypical characteristics via different mechanisms of action [6].…”

“…

BackgroundAntineoplastic activity has been previously shown for two isomeric flavones, 5,7-dihydroxy-3,6,8-trimethoxy flavone (flavone A) and 3,5-dihydroxy-6,7,8-trimethoxy flavone (flavone B), against colon cancer cell lines (Thomas et al in PLoS ONE 7:e39806, 5). Here, we present modified methods for the extraction and quantification of flavones A and B in rat colon tissue after intravenous dosing via high performance liquid chromatography, from the originally described procedure for extraction and quantification in rat plasma (Whitted et al in J Chromatogr B Analyt Technol Biomed Life Sci 1001:150–155, 7).

…”