Ginsenoside Rh4 induces apoptosis and autophagic cell death through activation of the ROS/JNK/p53 pathway in colorectal cancer cells

The use of ginsenosides in Cancer therapy has been intensively investigated. The ginsenoside Rh4 (Rh4), a rare saponin obtained from Panax notoginseng, dissolves in water more readily than total saponins, making this compound easier to use in anti-cancer pharmaceutics. Here, we investigated the antiproliferative activity and mechanisms of Rh4 in colorectal Cancer, both in vivo and in vitro. A colorectal Cancer xenograft model showed that Rh4 significantly inhibited tumor growth with few side effects. CCK-8 assays, flow cytometric analysis, Western blotting and immunohistochemistry revealed that Rh4 effectively suppressed colorectal Cancer cell proliferation via inducing G₀/G₁ phase arrest, caspase-dependent Apoptosis and autophagic cell death but was not significantly cytotoxic to normal colon epithelial cells. Furthermore, Apoptosis played a dominant role in Rh4-induced cell death, as the pan-caspase inhibitor Z-VAD-FMK blocked cell death to a greater extent than the Autophagy Inhibitor 3-methyladenine. Moreover, Rh4 increased Reactive Oxygen Species (ROS) accumulation and subsequently activated the JNK-p53 pathway. An ROS scavenger and JNK and p53 inhibitors significantly attenuated Rh4-induced Apoptosis and Autophagy. Thus, the present study is the first to illustrate that Rh4 triggers Apoptosis and Autophagy via activating the ROS/JNK/p53 pathway in colorectal Cancer cells, providing basic scientific evidence that Rh4 shows great potential as an anti-cancer agent.