Inhibitory effects of 3-bromopyruvate in human nasopharyngeal carcinoma cells

Abstract

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.

Efficacy of Dual Inhibition of Glycolysis and Glutaminolysis for Therapy of Renal Lesions in Tsc2+/− Mice

“…3-BrPA appeared to reduce the burden of renal carcinomas in Tsc2 +/− mice, but the reduction was not statistically significant. This finding is different from previous observations demonstrating antitumor efficacy of 3-BrPA for malignancies such as hepatocellular carcinoma, bladder cancer, nasopharyngeal carcinoma, and renal carcinoma in vitro and in vivo [12], [27], [28], [29]. Glycolytic inhibition with 2-deoxyglucose also effectively blocked tumor growth in a mouse model transplanted with Tsc2 -null rat tumor cells [10].…”

Topical 3-bromopyruvate is a novel targeted therapy for melanoma in a preclinical model

“…For this purpose, many models of 3BP delivery have been examined in animal studies. Routes of administration include intravenous [10,28], intraarterial [26,29], intraperitreal [16,30,31], intralesional [32][33][34] and inhaled [35]. Unfortunately, systemic delivery such as intravenous administration may be limited by the balance between therapeutic effects and toxicities to other organs.…”

Metabolic Reprogramming and Immune Evasion in Nasopharyngeal Carcinoma

“…HK is associated with NPC patient prognosis and outcomes, and its expression has been shown to be promoted by FOXC2-YAP signalling in NPC cells ( 20 , 21 ). HK inhibitors can limit tumor glycolysis and increase free radicals that result in cell apoptosis ( 22 , 23 ). The abnormal expression of PK enhances glucose uptake and increases the rate of phosphoenolpyruvate to pyruvate ( 18 ).…”