Corilagin induces the apoptosis of hepatocellular carcinoma cells through the mitochondrial apoptotic and death receptor pathways

Abstract

Corilagin, a gallotannin, is one of the major active components of many ethnopharmacological plants and exhibits antitumor, anti-inflammatory and antioxidative properties. In recent years, corilagin has provoked much attention due to its antitumor activity, yet the mechanisms attributed to its anticancer actions are largely unknown. In our previous research, our group reported that corilagin could inhibit the proliferation of hepatocellular carcinoma (HCC) cells by inducing G2/M phase arrest. In the present study, observation of the morphological changes showed that corilagin induced the apoptosis of HCC cells as determined by AO/EB and Hoechst 33258 staining assays. Furthermore, flow cytometric analysis was carried out to calculate the apoptotic rate which was 24.1% following treatment with corilagin (37.5 µM). At the molecular level, mitochondrial membrane potential assay and western blot analysis showed that the mitochondrial transmembrane potential was reduced and the rate of release of cytochrome c was increased, which led to the activation of caspase-9, caspase-3 and cleavage of PARP in the cytoplasm indicating activation of the mitochondrial apoptotic pathway. Moreover, following treatment with corilagin, we noted upregulation of Fas and FasL and activation of caspase-8 which represented activation of the death receptor pathway, and we also observed downregulation of Bcl-2 and survivin which was also attributed to the antitumor effect of corilagin. These results suggest that corilagin significantly induced the apoptosis of HCC cells through both the mitochondrial apoptotic pathway and the death receptor pathway, and corilagin is a potential complementary anticancer herbal drug for HCC therapy.

Metabolic heterogeneity of human hepatocellular carcinoma: implications for personalized pharmacological treatment

“…Six HCCs had an even more negative MMP than the normal hepatocyte. The MMP is a crucial model parameter because it largely determines the sensitivity of HCC to mitochondrial inhibitors such as corilagin, a natural plant polyphenol belonging to the class of hydrolyzable tannins, that may induce apoptosis of HCC by effectively depolarizing the MMP [49]. Our simulations suggested that four HCCs might be particularly susceptible to metformin‐induced energy impairment.…”

Corilagin in Cancer: A Critical Evaluation of Anticancer Activities and Molecular Mechanisms

“…P-Akt could enhance p21 Cip1 and p53 ubiquitylation and degradation, which act as inhibitors of cdc2/cyclin B1 proteins via the initiation of murine double minute 2 (Mdm2) and proliferating cell nuclear antigen (PCNA) [121,122]. Deng et al [123] observed that corilagin downregulated the expression of p-Akt while it upregulated p53 protein expression in the SMMC-7721 cell line in a concentration-dependent manner. Break down of caspase-9, caspase-3, and PARP was also detected, which supported the stimulation of the intrinsic apoptotic pathway.…”

“…Besides, caspase-8 is a vital protein of the extrinsic apoptotic pathways. Corilagin upregulated Fas and FasL signaling pathways, which in turn activated caspase-8 and thus triggered the extrinsic apoptosis pathway [123].…”

Corilagin induces apoptosis and autophagy in NRF2‑addicted U251 glioma cell line

“…Over the past decades, a number of studies have reported various pharmacological activities of corilagin, including anti-tumor activity ( 7 ), anti-oxidation activity ( 8 ), liver and lung protection ( 9 , 10 ) and anti-inflammatory activity ( 11 ). Other studies have noted that corilagin can inhibit various tumors such as gastric ( 12 ), liver ( 13 ), breast ( 14 ) and ovarian cancers ( 15 ). Corilagin not only directly inhibits tumor cell proliferation, but also indirectly exerts anti-tumor effects by enhancing the effect of traditional chemotherapy drugs ( 16 ).…”