title: 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.affiliation: Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui 233004, P.R. China.
authors.forename: Xue
authors.initials: X
authors.lastname: Zou
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui 233004, P.R. China.
authors.forename: Mengxiao
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui 233004, P.R. China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui 233004, P.R. China.
authors.forename: Surong
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui 233004, P.R. China.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Priority Research Center for Cancer Research, University of Newcastle, Callaghan, NSW 2308, Australia.
authors.forename: Xudong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Priority Research Center for Cancer Research, University of Newcastle, Callaghan, NSW 2308, Australia.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui 233004, P.R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002277:Carcinoma; D045744:Cell Line, Tumor; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011773:Pyruvates / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D011773:Pyruvates; D017382:Reactive Oxygen Species; C017092:bromopyruvate