Reduction of apoptosis by proanthocyanidin-induced autophagy in the human gastric cancer cell line MGC-803

Abstract

Proanthocyanidins are flavonoids that are widely present in the skin and seeds of various plants, with the highest content in grape seeds. Many experiments have shown that proanthocyanidins have antitumor activity both in vivo and in vitro. Autophagy and apoptosis of tumor cells induced by drugs are two of the major causes of tumor cell death. However, reports on the effect of autophagy induced by drugs in tumor cells are not consistent and suggest that autophagy can have synergistic or antagonistic effects with apoptosis. This research was aimed at investigating whether proanthocyanidins induced autophagy and apoptosis in human gastric cancer cell line MGC-803 cells and to identify the mechanism of proanthocyanidins action to further determine the effect of proanthocyanidins-induced autophagy on apoptosis. MTT assay was used to examine the proanthocyanidin cytotoxicity against human gastric cancer cell line MGC-803. Transmission electron microscopy and monodansylcadaverine (MDC) staining were used to detect autophagy. Annexin V APC/7-AAD double staining and Hoechst 33342/propidium iodide (PI) double staining were used to explore apoptosis. Western blotting was used to determine expression of proteins related to autophagy and apoptosis. Real-time quantitative PCR technology was used to determine the mRNA level of Beclin1 and BCL-2. The results showed that proanthocyanidins exhibit a significant inhibitory effect on the human gastric cancer cell line MGC-803 proliferation in vitro and simultaneously activate autophagy and apoptosis to promote cell death. Furthermore, when proanthocyanidin-induced autophagy is inhibited, apoptosis increases significantly, proanthocyanidins can be used together with autophagy inhibitors to enhance cytotoxicity.

Recent Advances in Anticancer Activities and Drug Delivery Systems of Tannins

“…However, in MGC‐803 human gastric cancer cells, PAs‐induced apoptosis was attenuated by PAs‐induced autophagy via reduction of PI3K/AKT/mTOR pathway, which was further confirmed by the addition of classical autophagy inhibitor 3‐methyladenine. After treatment with PAs (40.7 μg/mL) and 3‐methyladenine (5 mM), the inhibiton of autophagy by 3‐methyladenine could decrease Beclin 1 mRNA and increase Bcl‐2 mRNA, indicating that the block of PAs‐induced autophagy could significantly increase cell apoptosis …”

Oligomeric proanthocyanidins and epigallocatechin gallate aggravate autophagy of foam cells through the activation of Class III PI3K/Beclin1‐complex mediated cholesterol efflux

“…Genetic ablation of Class III PI3K leads to reflective cellular and organ damage which epitomize the essential role in regulating functional autophagy. 23 Studies on knockdown of either Class III PI3K or Beclin1 showed the decreased formation of autophagosomes through downregulated expression of LC3BII, with concomitantly increased accumulation of p62, aggregation and lipidation of LC3, and polyubiquitinated proteins showed the significant role of Class III PI3K/Beclin1 complex. 24 The proautophagic effect of Beclin1 was inhibited by the Beclin1/ Bcl-2 complex through the attenuation of the oligomerization of Beclin1/Class III PI3K complex, thereby impeding the formation of autophagosomes.…”

“…This complex subsequently stimulates the formation of autophagosomes in the foam cells. Genetic ablation of Class III PI3K leads to reflective cellular and organ damage which epitomize the essential role in regulating functional autophagy . Studies on knockdown of either Class III PI3K or Beclin1 showed the decreased formation of autophagosomes through downregulated expression of LC3BII, with concomitantly increased accumulation of p62, aggregation and lipidation of LC3, and polyubiquitinated proteins showed the significant role of Class III PI3K/Beclin1 complex .…”

Euptox A Induces G1 Arrest and Autophagy via p38 MAPK- and PI3K/Akt/mTOR-Mediated Pathways in Mouse Splenocytes

“…39 In addition, Chao Nie et al showed that procyanidins can induce autophagy in human gastric cancer cells but do not induce apoptosis. 40 In addition, Liao Fei showed that Euptox A has good antitumor activity. 41 Based on these data, we believe that Euptox A has the potential for use as a drug that promotes autophagy (similar to temozolomide) to kill apoptosis-resistant tumor cells by autophagic death.…”