Amentoflavone Stimulates Mitochondrial Dysfunction and Induces Apoptotic Cell Death in Candida albicans

Abstract

Amentoflavone was isolated from an ethyl acetate extract of the whole plant of Selaginella tamariscina. It is a traditional herb for the therapy of chronic trachitis and exhibits some anti-tumor activity. Previously, we confirmed the antifungal effects of amentoflavone. The objective of this study was to investigate the antifungal mechanism(s) of amentoflavone, such as mitochondria-mediated apoptotic cell death. The cells that were treated with amentoflavone exhibited a series of cellular changes that were consistent with apoptosis: externalization of phosphatidylserine, DNA and nuclear fragmentation, accumulation of intracellular reactive oxygen species (ROS) and hydroxyl radicals, and activation of metacaspase. In addition, diagnostic markers of apoptosis, including the reduction of mitochondrial inner-membrane potential and the release of cytochrome c from mitochondria, were observed. These phenomena are important changes in mitochondria-mediated apoptosis. Furthermore, the effect of thiourea as hydroxyl radical scavenger on amentoflavone-induced apoptosis was evaluated. A hydroxyl radical is a more active ROS species. Mitochondrial dysfunction was inhibited, which was indicated by decreased levels of intracellular hydroxyl radicals. Taken together, our results present the first evidence that amentoflavone induces apoptosis in C. albicans cells and is associated with the mitochondrial dysfunction. Besides, amentoflavone-induced hydroxyl radicals may play a significant role in mitochondria-mediated apoptosis.

Biflavonoids as Potential Small Molecule Therapeutics for Alzheimer’s Disease

“…3.1b) (Hwang et al 2013). Amentoflavone stimulates mitochondrial dysfunction and induces apoptotic cell death in yeast (Hwang et al 2012). The biflavonoid ginkgetin is cytotoxic to human ovarian adenocarcinoma and is also effective against the flu virus ( Kim et al 2008;Miki et al 2007).…”

Synergistic Effect of the Flavonoid Catechin, Quercetin, or Epigallocatechin Gallate with Fluconazole Induces Apoptosis in Candida tropicalis Resistant to Fluconazole

“…This fact can be explained by the ability of flavonoids to exhibit a prooxidant activity (52,53) that favors increased intracellular levels of hydroxyl radicals that lead to mitochondrial membrane damage. Hwang et al (55) showed that the flavonoid amentoflavone promotes mitochondrial dysfunction in C. albicans strains due to increased levels of ROS. Therefore, the flavonoids used synergistically with fluconazole in the present study seemed to indirectly promote the mitochondrial dysfunction as a result of increased levels of ROS.…”

Novel Antifungal Mechanism of Resveratrol: Apoptosis Inducer in Candida albicans

“…For example, a well-known anti-cancer compound amentoflavone, isolated from a traditional herb Selaginella tamariscina, showed antifungal activity through hydroxyl radical generation and mitochondrial dysfunction, followed by caspase activation [14]. Our present study investigated the antifungal activity of resveratrol against C. albicans, focusing its apoptotic mechanism.…”

“…Recent research on antifungal drugs has focused on the induction of endogenous programmed cell death of pathogenic fungal strains [14,19,27]. For example, a well-known anti-cancer compound amentoflavone, isolated from a traditional herb Selaginella tamariscina, showed antifungal activity through hydroxyl radical generation and mitochondrial dysfunction, followed by caspase activation [14].…”