Fludarabine reduces survivability of HepG2 cells through VEGF under hypoxia.
Fludarabine is the major drug against chronic lymphoblastic leukemia. However, the effects of fludarabine on solid tumors remain unclear. We reported previously that fludarabine inhibited expression of hypoxia-inducible factor 1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) in human ovarian cancer cells. The present study aims to investigate, (1) the mechanisms that fludarabine inhibits expression of HIF-1alpha and (2) the effects of fludarabine on tumor cells survival under hypoxia. Human hepatoma HepG2 cells were tested. We found that fludarabine reduced HIF-1alpha stability through prolyl hydroxylation. Fludarabine suppressed hypoxia-induced expression of VEGF and its receptor KDR. It inhibited VEGF-induced activation of AKT and ERK signaling and reduced hypoxia-enhanced HepG2 cell survivability. HepG2 cells were much more sensitive to fludarabine treatment under hypoxia than under nomoxia. These results suggest that fludarabine reduces survivability of HepG2 cells via VEGF signaling under hypoxia.
Xue
Jing
J
The Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Bi
Xinsheng
X
Wu
Guohao
G
Meng
Dan
D
Fang
Jing
J
D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*
D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D014740:Vidarabine; C024352:fludarabine; D010100:Oxygen