Increased ROS generation and p53 activation in α-lipoic acid-induced apoptosis of hepatoma cells

Abstract

Alpha-lipoic acid (alpha-LA) is an antioxidant used for the treatment of a variety of diseases, including liver cirrhosis, heavy metal poisoining, and diabetic polyneuropathy. In addition to its protective effect against oxidative stress, alpha-LA induces apoptosis in different cancer cells types. However, whether alpha-LA acid induces apoptosis of hepatoma cells is unknown. Herein, we investigated whether alpha-LA induces apoptosis in two different hepatoma cell lines FaO and HepG2. The results showed that alpha-LA inhibits the growth of both cell lines as indicated by the reduction in cell number, the reduced expression of cyclin A and the increased levels of the cyclin/CDKs inhibitors, p27(Kip1) and p21(Cip1). Cell cycle arrest was associated with cell loss, and DNA laddering indicative of apoptosis. Apoptosis was preceded by increased generation of reactive oxygen species, and associated with p53 activation, increased expression of Bax, release of cytochrome c from mitochondria, caspases activation, decreased levels of survivin, induction of pro-apoptotic signaling (i.e JNK) and inhibition of anti-apoptotic signaling (i.e. PKB/Akt) pathways. In conclusion, this study provides evidence that alpha-LA induces apoptosis in hepatoma cells, describes a possible sequence of molecular events underlying its lethal effect, and suggests that it may prove useful in liver cancer therapy.

The effect of alpha lipoic acid on the developmental competence of mouse isolated preantral follicles

“…In support of our results, long time exposure to ALA results in increase of lipid peroxidation, mitochondrial damage and inhibition of glycogen synthesis [17,36]. Also, it has been shown that high dose of ALA could arrest cell cycles in some cells [35,55] or could provoke cell death through internucleosomal DNA fragmentation and caspase cleavage in numerous cancer cell lines [48,55,57]. Hence, it appears that high doses of ALA more than 100 uM are toxic for isolated preantral follicles.…”

“…This observation may give explanation about our finding which why increasing of ALA concentrations results in decrease developmental competence of isolated follicles. In addition, as previous mentioned, high dose of ALA in numerous cancers cell lines could induce apoptosis [35,48,55,57] which explicates, high degeneration rate of follicles in the presence of high concentrations of ALA.…”

The Risk Evaluation of Tungsten Oxide Nanoparticles in Cultured Rat Liver Cells for Its Safe Applications in Nanotechnology

“…Hsin et al (2008) found that nano silverinduced apoptosis was mediated by the ROS via JNK and p53 activation. ROS could also directly activate p53, most probably by the induction of DNA damage (Simbula et al 2007;Turkez and Togar 2010;Turkez and Geyikoglu 2010;Turkez et al 2012). Based on the results of Liu and Sun (2010), the following silica nanoparticles-mediated signaling pathways for apoptosis related events were proposed as ROS production (JNK/c-Jun phosphorylation), P53 activation, Bax up regulation and Bcl-2 down regulation.…”

RIP3 overexpression sensitizes human breast cancer cells to parthenolide in vitro via intracellular ROS accumulation

“…The dramatic increase in ROS levels and the disruption of the antioxidant balance result in oxidative damage to cellular structures, signal transduction www.chinaphar.com Lu C et al Acta Pharmacologica Sinica npg changes and cell death [29] . Many studies have reported that ROS induce apoptosis in various cancer cells [30][31][32] . Our experiments demonstrated that RIP3 gene transfection enhanced the PTL-induced generation of intracellular ROS in MCF-7 and MDA-MB-231 cells.…”