The molecular mechanism of ginsenoside Rh2 and its octyl ester derivative on antiangiogenesis in cancer treatment: The battle between PI3K and ROS

Background: The cancer treatments that target tumor associated angiogenesis (TAA) induced by vascular endothelialgrowth factor A (VEGFA) have become valued. Ginsenoside Rh2 has been proved to inhibit TAA throughVEGFA. However, the underlying mechanisms remain unclear. Moreover, the octyl ester derivative of Rh2 (Rh2-O) exhibited better inhibitory effects than Rh2 on liver cancer in our previous researches, which indicated thatRh2-O might also exert inhibitory effects on TAA. Purpose: To explore the inhibitory effects of Rh2 and Rh2-O on TAA and to investigate the underlyingmechanisms. Method: The inhibitory effects of Rh2 and Rh2-O on TAA were evaluated by conditioned medium, co-culture, andtumor-bearing mice. The network pharmacology was used to explore the possible targets, which were subsequentlyverified by specific agonists or inhibitors. Results: Rh2 and Rh2-O could efficiently inhibit TAA in a dose-dependent manner (P < 0.05). Moreover, theenhancement on phosphorylation of PI3K and STAT3 could reverse the inhibitory effects of Rh2 and Rh2-O onTAA while N-acetylcysteine could improve the effects (P < 0.05). Conclusion: Rh2 and Rh2-O could inhibit TAA via inhibiting the VEGFA, which was mediated by PI3K/STAT3 andPI3K/HIF-1α pathway. Meanwhile the generation of ROS could be a foe for Rh2 and Rh2-O to inhibit TAA.