Novel herbal flavonoids promote apoptosis but differentially induce cell cycle arrest in human colon cancer cell

Abstract

Formononetin is a novel herbal isoflavonoid isolated from Astragalus membranaceus, a medicinal plant that possesses antitumorigenic property. We attempted to compare the anticarcinogenic mechanism of formononetin with that of the known proapoptotic flavonoid isoliquiritigenin (ISL) in human cancer cells. We first evaluated the effects of formononetin and ISL on HCT 116 colon cancer cell viability. Immunofluorescence staining was then performed to observe the morphological changes of cancer cells undergoing apoptosis, which had been substantiated using Annexin V-FITC/propidium iodide staining. Western immunoblotting and flow cytometry were also employed to study parameters associated with apoptosis and cell proliferation. Our data show that formononetin and ISL both inhibited the growth of colon cancer cells and promoted apoptosis. These processes were accompanied by caspase activation and downregulation of the antiapoptotic proteins Bcl-2 and Bcl-x(L). Besides, the novel proapoptotic protein NSAID-activated gene (NAG-1) and its upstream regulator were overexpressed in drug-treated cells. Nevertheless, only ISL was found to induce a G2 arrest. These findings exemplify that both formononetin and ISL could cause growth inhibition and facilitate apoptosis in colon cancer cells, while only ISL is capable of inducing phase-specific cell cycle arrest. This suggests that the anticarcinogenic activities of different herbal flavonoids may involve both common and differential mechanisms of action, which could be developed as potential anticancer drugs.

Eupatilin: A flavonoid compound isolated from the artemisia plant, induces apoptosis and G2/M phase cell cycle arrest in human melanoma A375 cells

“…For example, Eupatilin induced gastric carcinoma AGS cells at G1 phase (Choi et al, 2009). The result of Eupatilin in inducting cell cycle arrest at G2/M phase is also consistent with other studies that some other flavonoid compounds arrest cell cycle at G2/M phase (Auyeung and Ko, 2010;Priyadarsini et al, 2008).…”

“…It is reported that flavonoid has the potential to arrest cell cycle in a variety of cancer cells (Auyeung and Ko, 2010;Drees et al, 1997;Priyadarsini et al, 2010;Wang et al, 2000). Several studies have indicated that for persistence of a normal cell cycle, cells undergo certain cell cycle check points for the surety of proper accomplishment of different events of cell cycle and for the protection of dividing cells as a result of severely damaged DNA (Singh and Khar, 2006;Tse et al, 2007).…”

Formononetin Promotes Cell Cycle Arrest via Downregulation of Akt/Cyclin D1/CDK4 in Human Prostate Cancer Cells

“…As a typical phytoestrogen, formononetin has been demonstrated to possess a wide range of biological activities including antioxidant, antiviral and cardioprotective effects [10]. Remarkably, some other studies reported formononetin-induced tumor cell apoptosis in some cancer types in vitro and in vivo [11,12,13,14]. For instance, it was shown that formononetin could induce mitochondrial apoptosis in PCa cells via downregulation of IGF-1/IGF-1R signaling pathway, implying the potential application of formononetin in antitumor therapy against prostate cancer [15].…”

A flavonoid compound fromChrysosplenium nudicauleinhibits growth and induces apoptosis of the human stomach cancer cell line SGC-7901

“…Flavonoids were generally recognized as antioxidants, which were found to induce cancer cell apoptosis through caspase activation (Shanker et al, 2007) or the downregulation of antiapoptotic proteins Bcl-2 and Bcl-x(L) (Auyeung & Ko, 2010). However, the anticancer activity and precise mechanism of TTF in vivo remain unknown, and further studies are necessary to address these issues.…”