Tetrandrine induces G1/S cell cycle arrest through the ROS/Akt pathway in EOMA cells and inhibits angiogenesis in vivo

Abstract

Tetrandrine, a bisbenzylisoquinoline alkaloid, is known to inhibit tumor cell proliferation and induce apoptosis in cancer models in vitro and in vivo. In the present study, tetrandrine significantly inhibited the proliferation of mouse endothelial cells (EOMA cell) and induced G1/S arrest in EOMA cells, in which the expressions of cyclin D and cyclin E and CDKs were downregulated. Tetrandrine treatment also caused intracellular accumulation of reactive oxygen species (ROS). Pretreatment with NAC, which is a ROS inhibitor, blocked G1/S cell arrest and cyclin regulation induced by tetrandrine, implying that ROS generation plays an important role in tetrandrine-induced cell cycle arrest. Furthermore, a decreased phospho-Akt protein level after tetrandrine treatment was reversible with the removal of the intracellular ROS by NAC. Notably, overexpression of Akt decreased tetrandrineinduced G1/S arrest. Finally, we verified the antiangiogenic effects of tetrandrine in vivo in a liver cancer xenograft model in nude mice. In conclusion, tetrandrine inhibits EOMA cell growth through the ROS/Akt pathway, and it could be a promising compound for cancer therapy as an inhibitor of tumor vascular growth.

Dammarane-type triterpene ginsenoside-Rg18 inhibits human non-small cell lung cancer A549 cell proliferation via G1 phase arrest

“…However, ROS overproduction can be toxic to cells owing to their peroxidative activity (10). One proposed anticancer strategy is the use of exogenous ROS-stressing agents or inhibition of endogenous antioxidants to elevate intracellular ROS levels to toxic amounts, triggering cell cycle arrest in the target cancer cell (11). Ginsenosides are triterpene saponins and the major pharmacologically active components extracted from the roots and rhizomes of various Panax species.…”

“…. ROS are involved in multiple types of chemically induced cell cycle arrest; evidence indicates that increased oxidative stress is associated with cell cycle arrest induced by certain anticancer agents (11,30). Among the protopanaxadiols, ginsenoside-Rb 2 has been demonstrated to significantly increase the expression of genes encoding antioxidant enzymes, including superoxide dismutase and catalase in vitro (31).…”

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

“…Recently, in mouse endothelial cells (EOMA cells), tetrandrine exhibited significant proliferation inhibition and G1/S arrest via down-regulated expression of cyclin D, cyclin E and CDKs. Furthermore, intracellular accumulation of reactive oxygen species (ROS) and the decline of phospho-Akt protein levels play an important role in tetrandrine-induced cell cycle arrest [28]. Specifically, tetrandrine inhibits the proliferation of SUM-149 and SUM-159 breast cancer initiation cells (TICs).…”

“…Other studies revealed that tetrandrine was capable of triggering apoptosis in 5637 and T24 human bladder cancer cells and in 786-O, 769-P and ACHN human RCC cells in vitro , which was accompanied by the activation of a very strong and prominent caspase cascade and the mitochondrial pathway in a concentration-dependent manner [27, 48]. Additionally, tetrandrine effectively induced the apoptosis of glioma cells in concentration- and time-dependent manners [49] and induced the apoptosis of EOMA cells in vitro and in vivo [28]. …”

“…Moreover, tetrandrine significantly inhibited endothelial cell proliferation, adhesion, migration, invasion, and tube formation by targeting vascular endothelial growth factor, hypoxia-inducible factor-1, integrin 5, endothelial cell specific molecule-1, and intercellular adhesion molecule-1 in vivo [61]. As an inhibitor of tumor vascular growth, tetrandrine was verified to have antiangiogenic effects in vivo in a liver cancer nude mice xenograft model [28] and significantly weakened the migration and invasion capacity of DU145 and PC-3 human prostate cancer cells [38]. …”