7,7′′‐Dimethoxyagastisflavone‐induced Apoptotic or Autophagic Cell Death in Different Cancer Cells

Abstract

7,7''-Dimethoxyagastisflavone (DMGF), a biflavonoid isolated from the needles of Taxus × media cv. Hicksii, was evaluated for its antiproliferative and antineoplastic effects in three human cancer cell lines. Interestingly, DMGF caused cell death via different pathways in different cancer cells. DMGF induced apoptosis, activated caspase-3 activity and changed the mitochondrial membrane potential in HT-29 human colon cancer cells. However, the apoptotic pathway is not the major pathway involved in DMGF-induced cell death in A549 human lung cancer cells and HepG2 human hepatoma cells. Treatment with 3-MA, an inhibitor of autophagy, significantly decreased DMGF-induced cell death in HepG2 and A549 cells, but did not affect DMGF-induced cell death in HT-29 cells. Following DMGF treatment, the HepG2 cells increased expression of LC3B-II, a marker used to monitor autophagy in cells. Thus, DMGF induced apoptotic cell death in HT-29 cells, triggered both apoptotic and autophagic death in A549 cells and induced autophagic cell death in HepG2 cells.

The inhibitory effect of 7,7″-dimethoxyagastisflavone on the metastasis of melanoma cells via the suppression of F-actin polymerization

“…DMGF is a bioactive biflavonoid from Ouratea parviflora [ 6 ] or Taxus media var. Hicksii [ 7 ]; however, little is known about its functions in tumor angiogenesis, metastasis and tumor growth except for its effect on inducing tumor death through apoptosis or autophagy in different cancer cells [ 7 ]. In this study, the DMGF was shown to dramatically suppress the spontaneous metastasis of B16F10 melanoma cells from subcutaneous sites to the spleen (Figure 4 ).…”

“…Therefore, SVEC4-10 is sensitive as B16F10 cells. However, in our previous results, DMGF had different antiproliferative effects between cancer cell lines and primary cells, including human PBMCs and mouse splenocytes [ 7 ]. These results showed that DMGF has selective cytotoxicity between normal and tumor cells.…”

“…DMGF (98% purity by high performance liquid chromatography) isolated from the dried needles of Taxus media var. Hicksii was kindly provided by Yung-Shin Pharmaceutical Industry Co., Ltd. (Taichung, Taiwan) [ 7 ]. Briefly, the dried needles of Taxus media var.…”

“…For example, the amentoflavone derived from Selaginella tamariscina or Torreya nucifera has been shown to not only have potent anti-candidal or anti-SARS-coV activities [ 2 , 3 ], but also exhibits anti-neovascularization by interfering in the interaction of VEGF and VEGFR-1 [ 4 , 5 ]. In addition, 7,7″-dimethoxyagastisflavone (DMGF, the structure was shown as Figure 1A ) has been found to have anti-HSV-1 and -HSV-2 activity [ 6 ], and it can cause the cell death via apoptosis or autophagy [ 7 ]. Moreover, ginkgetin is a strong NF-κB inhibitor (IC50 = 7.5 μM) [ 8 ], and it selectively inhibits the growth of human ovarian adenocarcinoma [ 9 ].…”

Novel Insights into the Pharmacology of Flavonoids

“…However, some studies have reported inconclusive associations (Romagnolo and Selmin, ). Flavonoids such as quercetin (Yang, et al ., ), rutin (Marrassini et al ., ), hesperetin (Aranganathan and Nalini, ), xanthohumol (Zajc et al ., ), 7,7''‐dimethoxyagastisflavone (Hwang et al ., ), silymarin (Yu et al ., ), chrysoplenetin and chrysosplenol D (from Vitex negundo ) (Awale et al ., ), formononetin, genistein (Mansoor et al ., ), peonidin and cyaniding (two anthocyanidins) (Tanaka et al ., ) and many others isolated from a number of medicinal plants such as Marrubium thessalum (Argyropoulou et al ., ), Zeyheria montana (Seito et al ., ), Spatholobus suberectus (Shim, ) and Glycine max (Goh et al ., ), as well as related polyphenolic compounds such as rotenoids (Aviello et al ., ; Kang et al ., ), anthraquinones (Capasso et al ., ; Dibwe et al ., ; Lee et al ., , ; Aviello et al ., ) and resveratrol (Lim et al ., ) have recently been shown to exert genoprotective, cytotoxic, antiproliferative and/or proapoptotic actions in different tumoural cell lines. More in‐depth studies have shown that liquiritigenin, a flavanone found in a variety of plants including licorice, promoted apoptosis in HeLa cells, an effect associated with the up‐regulation of p53 and Bax, down‐regulation of Bcl‐2 and surviving, release of cytochrome c and elevated activity of caspase‐9 and ‐3 (Liu et al ., ).…”