Preferential inhibition of hepatocellular carcinoma by the flavonoid Baicalein through blocking MEK-ERK signaling

Abstract

Abstract. Baicalein is a purified flavonoid extracted from the roots of Scutellaria baicalensis or Scutellaria radix. Although previous studies have suggested that Baicalein possesses an in vitro anti-hepatocellular carcinoma activity, its in vivo effects and mechanisms of action are still not completely understood. In this study, Baicalein at concentrations of 40-120 µM exhibited significant cytotoxicity to three hepatocellular carcinoma (HCC) cell lines but marginal cytotoxicity to a normal liver cell line in vitro. Compared to a standard chemotherapy drug, 5-fluorouracil (5-FU), Baicalein had greater effect on HCC cells but less toxicity on normal liver cells. Treatment with Baicalein dramatically reduced mitochondrial transmembrane potential, and activated caspase-9 and caspase-3. Blockade of Baicaleininduced apoptosis with a pan-caspase inhibitor partially attenuated Baicalein-induced growth inhibition in HCC. Baicalein treatment significantly inhibited tumor growth of HCC xenografts in mice. Induction of apoptosis was demonstrated in Baicalein-treated xenograft tumors by the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Furthermore, Baicalein treatment dramatically decreased the levels of phosphorylation of MEK1, ERK1/2 and Bad in vitro and in vivo. Overexpression of human MEK1 partially blocked Baicalein-induced growth inhibition. Consequently, these findings suggest that Baicalein preferentially inhibits HCC tumor growth through inhibition of MEK-ERK signaling and by inducing intrinsic apoptosis. IntroductionHepatocellular carcinoma (HCC) is one of the common cancers in Asia and Africa. The incidence of HCC is increasing in Europe and the United States (1). Although HCC can be cured at the early stage by surgical resection, most patients can not be diagnosed at the early stage since tumors are asymptomatic (2). Current treatment options for HCC patients at the late stage include chemotherapy, chemoembolization, ablation, and proton beam therapy. These treatment options remain disappointed in clinic. HCC patients will relapse and rapidly progress to the advanced stages with vascular invasion and multiple metastases, which lead to a low 5-year survival rate of less than 7% (3). HCC patients who have surgically resectable localized tumors show a better prognosis. However, even these patients have a dismal 5-year survival rate of 15 to 39% (4). Clearly, there is an urgent need to search for new therapies for this lethal disease.We have reported that chrysanthemum indicum extract (CIE), a Chinese herbal extraction, exerts a significantly inhibitory effect on HCC cells (MHCC97H) in previous studies (5,6). One particular point to stress is that CIE appeares to have no cytotoxic effect on normal liver cells, highlighting an advantage of the herbal treatment. Herbal medicine flavonoids have recently received increasing attention because of the beneficial effects of anti-tumor and

Chrysin, baicalein and galangin are indirect activators of the human constitutive androstane receptor (CAR)

“…Several studies in the past have shown that chrysin exerts an inhibition effect on the ERK signaling cascade in different cells and thus suppresses the levels of active phosphorylated ELK1 (Gao et al, 2013;Pichichero et al, 2011). Similarly, baicalein has been reported to have an inhibitory effect on ERK1/2 phosphorylation in both in vivo and in vitro (Agarwal et al, 2009;Gao et al, 2013;Chen et al, 2013;Liang et al, 2012;Zhou et al, 2013). On the other hand opposite effects have also been reported for baicalein, baicalin and galangin, suggesting cellor tissue-specific effects (Chen et al, 2006;Lei et al, 2012;Liu et al, 2013;Zhou et al, 2009).…”

Effect of IL-17A on the Migration and Invasion of NPC Cells and Related Mechanisms

“…Apoptotic and/or necrotic cells were evaluated by Annexin V binding and propidium iodide (PI) uptake using an Annexin V-FITC/PI kit as previously described [13]. Briefly, NPC-039 cells were plated at a density of 5×10 4 cells per well into 6-well plates for 12 h. The cells were treated with various concentrations of IL-17A (0 and 50 ng/ml) and incubated at 37°C for 24 h. The cells were washed with cold PBS and resuspended in Annexin V binding buffer.…”

Natural Products for the Prevention and Treatment of Hangover and Alcohol Use Disorder

“…Baicalein possessed anti-hepatocellular carcinoma activity in vitro and in vivo. Baicalein at the concentrations of 40-120 μM exerted cytotoxicity to three hepatocellular carcinoma cell lines but with little cytotoxicity to a normal liver cell line in vitro [124]. In addition, baicalin has potential beneficial effects on ischemia/reperfusion (I/R) injury in alcoholic fatty liver.…”