Tetrandrine is a potent cell autophagy agonist via activated intracellular reactive oxygen species

Abstract

BackgroundAutophagy is an evolutionarily conserved cellular process that involves the lysosomal degradation of proteins and organelles and the recycling of cellular components to ensure cellular survival under external or internal stress. Numerous data has indicated that autophagy can be successfully targeted for the treatment of multiple cancers. We have previously demonstrated that tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the broadly used Chinese medicinal herb Stephaniae tetrandrae, exhibits potent antitumor effects when used either alone or in combination with other drugs.ResultsIn the present study, we showed that tetrandrine is a broad-spectrum potent autophagy agonist. Although low-dose tetrandrine treatment does not affect cell viability, it can potently induce autophagy in a variety of cell lines, including cancerous cells and nontumorigenic cells. The autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ), effectively blocked tetrandrine-induced autophagy. Moreover, tetrandrine significantly triggered the induction of mitophagy. The underlying mechanisms are associated with the tetrandrine-induced production of intracellular reactive oxygen species (ROS), which plays a critical role in tetrandrine-induced autophagy.ConclusionsHere, we report that tetrandrine is a potent cell autophagy agonist and may have a wide range of applications in the fields of antitumor therapy and basic scientific research.

Synergistic anti‐tumour effects of tetrandrine and chloroquine combination therapy in human cancer: a potential antagonistic role for p21

“…a crucial target for cancer treatments has recently received considerable attention (Ma et al, 2013). We previously reported that tetrandrine induced autophagy through regulation of autophagy-related gene 7 (ATG7) expression and ROS/extracellular signal-regulated kinase in human hepatocellular carcinoma (Gong et al, 2012a;Wang et al, 2015). As a mechanism for cell survival, autophagy triggers cells to degrade unnecessary proteins and organelles to obtain a source of macromolecular precursors to prevent the cells from dying when they are under adverse stress, such as nutrient starvation or exposure to chemotherapeutic agents.…”

Tetrandrine triggers an alternative autophagy in DU145 cells

“…Tetrandrine (Tet), a natural product isolated from Stephania tetrandra, has been reported to be an anti-tumor and anti-inflammatory drug (1)(2)(3)(4)(5)(6)(7)(8). Previously, the present authors have demonstrated that Tet induces cell death in 11 cancer cell lines (1).…”

“…Autophagy has an important role in Tet-induced cell death (1,3). In order to explore the role of autophagy in Tet-induced cell death of DU145 cells, the LC3 conversion was measured using western blotting.…”

“…Tet directly neutralizes the lysosomal acidity, blocks the autophagic flux in the degradation step and causes energetic impairment, which eventually results in cell death (1). By contrast, Tet also acts as an autophagy agonist by inducing the synthesis of reactive oxygen species (3,4,(9)(10)(11), indicating that Tet may function as a multi-target drug to regulate autophagy in cancer cells. Regardless of the Tet target, the present authors and other groups have previously consistently observed that Tet increases the number of autophagosomes, levels of microtubule-associated protein 1 light chain 3, type II (LC3-II) and the number of enhanced green fluorescent protein-LC3 puncta in cancer cells (1,3,9).…”

Tetrandrine, a Chinese plant-derived alkaloid, is a potential candidate for cancer chemotherapy

“…Tetrandrine has been proven to be a potent broad-spectrum autophagy agonist with effects on a variety of cell lines, including MCF-7, HeLa, PC3, U87, MDA-MB-231, and A549 cancer cells, and HFF and HEK 293 nontumorigenic cells, and it exhibits a much stronger activity in inducing autophagy than the autophagy activator rapamycin [69]. Additionally, tetrandrine has the capability to induce autophagy in human hepatocellular carcinoma Huh7, BEL7402, HepG2, and L02 cells in vitro and in vivo , and the autophagy-inducing activity is at least partially dependent on the accumulation of intracellular ROS and the repression of ATG7 [70].…”