Paclitaxel induces vascular endothelial growth factor expression through reactive oxygen species production.
The antineoplastic drug paclitaxel is known to block cells in the G2/M phase of the cell cycle through stabilization of microtubules. The development of paclitaxel resistance in tumors is one of the most significant obstacles to successful therapy. Vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 (HIF-1) are important regulators of neovascularization. HIF-1 regulates VEGF expression at the transcriptional level. Here, we investigated whether paclitaxel treatment affects VEGF expression for the development of paclitaxel resistance. Paclitaxel treatment induced dose-dependent cell death and increased VEGF expression. Paclitaxel also induced nuclear factor-kappaB activation and stabilized HIF-1alpha, which stimulated luciferase activity of HIF-1alpha response element on VEGF gene. As paclitaxel treatment produced reactive oxygen species (ROS), VEGF expression was increased by H2O2 treatment and reduced by various ROS scavengers such as N-acetyl-L-cysteine, pyrrolidine dithiocarbamate and diphenylene iodonium. Paclitaxel-induced cell death was aggravated by incubation with those ROS scavengers. Collectively, this suggests that paclitaxel-induced VEGF expression could be mediated by paclitaxel-induced ROS production through nuclear factor-kappaB activation and HIF-1alpha stabilization, which could affect resistance induction to antitumor therapeutics during cancer treatment.
Kim
Hyun Sun
HS
Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea.
Oh
Jin Mi
JM
Jin
Dong Hoon
DH
Yang
Kyu-Hwan
KH
Moon
Eun-Yi
EY
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000378:metabolism; D008156:Luciferases / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects* / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D006861:Hydrogen Peroxide; D008156:Luciferases; D017239:Paclitaxel