Inhibitory effects of 3-bromopyruvate in human nasopharyngeal carcinoma cells.

Abstract

Tumor cells depend on aerobic glycolysis for adenosine triphosphate (ATP) production, which is therefore targeted by therapeutic agents. The compound 3-bromopyruvate (3-BrPA), a strong alkylating agent and hexokinase inhibitor, inhibits tumor cell glycolysis and the production of ATP, causing apoptosis. 3-BrPA induces apoptosis of nasopharyngeal carcinoma (NPC) cell lines HNE1 and CNE-2Z, which may be related to its molecular mechanisms. In the present study, we investigated the effects of 3-BrPA on the viability, reactive oxygen species (ROS), apoptosis and other types of programmed cell death in NPC cells in vitro and in vivo. PI staining showed significant apoptosis in NPC cells accompanied by the overproduction of ROS and downregulation of mitochondrial membrane potential (MMP, ΔΨm) by 3-BrPA. However, the ROS scavenger N-acetyl-L-cysteine (NAC) significantly reduced 3-BrPA-induced apoptosis by decreasing ROS and facilitating the recovery of MMP. We elucidated the molecular mechanisms underlying 3-BrPA activity and found that it caused mitochondrial dysfunction and ROS production, leading to necroptosis of NPC cells. We investigated the effects of the caspase inhibitor z-VAD-fmk, which inhibits apoptosis but promotes death domain receptor (DR)-induced NPC cell necrosis. Necrostatin-1 (Nec-1) inhibits necroptosis, apparently via a DR signaling pathway and thus abrogates the effects of z-VAD‑fmk. In addition, we demonstrated the effective attenuation of 3-BrPA-induced necrotic cell death by Nec-1. Finally, animal studies proved that 3-BrPA exhibited significant antitumor activity in nude mice. The present study is the first demonstration of 3-BrPA-induced non-apoptotic necroptosis and ROS generation in NPC cells and provides potential strategies for developing agents against apoptosis‑resistant cancers.

• Authors: Xue Zou, Mengxiao Zhang, Yiming Sun, Surong Zhao, Yingmei Wei, Xudong Zhang, Chenchen Jiang, Hao Liu
• Journal: Oncology reports (Oncol Rep) Vol. 34 Issue 4 Pg. 1895-904 (Oct 2015) ISSN: 1791-2431 [Electronic] Greece
• PMID: 26239511 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Pyruvates
• Reactive Oxygen Species
• bromopyruvate

Topics

• Animals
• Apoptosis (drug effects)
• Carcinoma
• Cell Line, Tumor
• Humans
• Membrane Potential, Mitochondrial
• Mice
• Mitochondria (drug effects, pathology)
• Nasopharyngeal Carcinoma
• Nasopharyngeal Neoplasms (drug therapy, genetics, pathology)
• Pyruvates (administration & dosage)
• Reactive Oxygen Species (metabolism)
• Xenograft Model Antitumor Assays