Low Nanomolar Concentrations Of Cucurbitacin-I Induces G2/M Phase Arrest And Apoptosis By Perturbing Redox Homeostasis In Gastric Cancer Cells In Vitro And In Vivo

Background:Chemotherapy has been the common treatment for those patients with advanced gastric cancers.The number of patients who benefit from treatment is,however,still rather limited.Thus there is clearly an urgent need to develop more efficacious therapeutics to treat advanced gastric cancers.This study reports the evaluation of Cucurbitacin-I,a potent selective inhibitor of JAK2/STAT3 signaling pathway with anti-proliferative and anti-tumor properties,as a therapy against gastric cancer.Purpose:To study the underlying molecular mechanisms of anti-gastric cancer activity of Cucurbitacin-I both in vitro and in vivo.Experimental Design:The anti-tumor activity of Cucurbitacin-I was determined in proliferation,cell cycle arrest,apoptosis assays.Related pathways were identified by western blotting.Cucurbitacin-I efficacy in vivo was assessed by HGC-27 xenograft tumor regrowth delay,xenograft lysate biochemistry analysis,and tissue section immunohistochemistry.Results:Cucurbitacin-I markedly inhibits gastric cancer cell growth by inducing G2/M phase cell cycle arrest and apoptosis at low nanomolar concentrations via a STAT3-independent mechanism.Notably,Cucurbitacin-I significantly decreases intracellular GSH/GSSG ratio through inhibiting NRF2 pathway to break cellular redox homeostasis,and subsequently induces the expression of GADD45a in a p53-independent manner,and activates JNK/p38 MAPK signaling.Moreover,Cucurbitacin-I-induced GADD45a and JNK/p3 8 MAPK signaling form a positive feedback loop and can be reciprocally regulated by each other.Conclusions:The present study provides new insights into the mechanisms of anti-tumor effects of Cucurbitacin-I,supporting Cucurbitacin-I as an attractive therapeutic drug in gastric cancer through modulating the redox balance.