3-Bromopyruvic acid is an antitumor agent able to inhibit aerobic glycolysis and oxidative phosphorylation, with IC50 values of 15 and 35μM for pyruvate dehydrogenase (PDH) and isocitrate dehydrogenase (IDH), respectively[1]. 3-Bromopyruvic acid covalently modifies hexokinase II (HEK II) and the dissociation of HEK II from mitochondria [2]. In the model of malignant tumor cells, 3-Bromopyruvic acid is used as an inhibitor of ATPase activity, which reduces ATP levels and counteracts drug efflux by acting on ATP-binding cassette transporters to reverse chemotherapy resistance[3].
In vitro, 3-Bromopyruvic acid treatment at a concentration of 25μg/ml for 48 hours led to the appearance of typical apoptotic morphological features in MCF-7 cells, including nuclear shrinkage, excessive cytoplasmic granules, and significant reductions in the expression of Bcl-2, c-Myc, and mutant p53[4]. Treatment with 3-Bromopyruvic acid (40μM) for 2 hours led to a significant decrease in the viability of U118 glioblastoma cells, and an increase in reactive oxygen species (ROS) produced in the mitochondria[5]. Treatment with 100μM 3-Bromopyruvic acid for 12 hours induced DNA breaks in THP-1 cells, thereby triggering phosphorylation of H2A.X[6].
In vivo, 3-Bromopyruvic acid treatment via intraperitoneal injection (20mg/kg; every other day for 30 days) significantly reduced tumor growth in the pancreatic cancer model of mice, prolonged the survival time of mice, led to a significant decrease in the number of myeloid suppressor cells in tumor tissues, and increased the infiltration of CD8+ T cells[7]. Intraperitoneal injection of 3-Bromopyruvic acid (8mg/kg), every 4 days, for 28 consecutive days, significantly inhibited tumor progression in the SW480 cell-xenograft mouse model, resulting in disordered vascular distribution in the tumor tissue, shrinkage of cell nuclei, and infiltration of inflammatory cells[8].
References:
[1] Jardim-Messeder D, Moreira-Pacheco F. 3-Bromopyruvic acid inhibits tricarboxylic acid cycle and glutaminolysis in HepG2 cells[J]. Anticancer research, 2016, 36(5): 2233-2241.
[2] Chen Z, Zhang H, Lu W, et al. Role of mitochondria-associated hexokinase II in cancer cell death induced by 3-bromopyruvate[J]. Biochimica et Biophysica Acta (BBA)-Bioenergetics, 2009, 1787(5): 553-560.
[3] Shoshan M C. 3-Bromopyruvate: targets and outcomes[J]. Journal of bioenergetics and biomembranes, 2012, 44(1): 7-15.
[4] Liu X, Zheng X, Wang Y. Inhibitive effect of 3-bromopyruvic acid on human breast cancer MCF-7 cells involves cell cycle arrest and apoptotic induction[J]. Chinese medical journal, 2009, 122(14): 1681-1685.
[5] Petricciuolo M, Davidescu M, Fettucciari K, et al. The efficacy of the anticancer 3-bromopyruvate is potentiated by antimycin and menadione by unbalancing mitochondrial ROS production and disposal in U118 glioblastoma cells[J]. Heliyon, 2020, 6(12).
[6] Cal M, Matyjaszczyk I, Litwin I, et al. The anticancer drug 3-bromopyruvate induces DNA damage potentially through reactive oxygen species in yeast and in human cancer cells[J]. Cells, 2020, 9(5): 1161.
[7] Roy S, Dukic T, Bhandary B, et al. 3-Bromopyruvate inhibits pancreatic tumor growth by stalling glycolysis, and dismantling mitochondria in a syngeneic mouse model[J]. American Journal of Cancer Research, 2022, 12(11): 4977.
[8] Sun Y, Liu Z, Zou X, et al. Mechanisms underlying 3-bromopyruvate-induced cell death in colon cancer[J]. Journal of bioenergetics and biomembranes, 2015, 47(4): 319-329.
3-Bromopyruvic acid是一种抗肿瘤剂，能够抑制有氧糖酵解和氧化磷酸化过程，对丙酮酸脱氢酶（PDH）和异柠檬酸脱氢酶（IDH）的IC50值分别为15μM和35μM[1]。3-Bromopyruvic acid通过共价修饰己糖激酶II（HK II）并促使HK II从线粒体解离发挥作用[2]。在恶性肿瘤细胞模型中，3-Bromopyruvic acid作为ATP酶活性抑制剂，可降低ATP水平并通过作用于ATP结合盒转运蛋白拮抗药物外排，从而逆转化疗耐药性[3]。
在体外，25μg/ml 的3-Bromopyruvic acid处理48小时可诱导MCF-7细胞出现典型凋亡形态特征（包括核固缩、胞质颗粒增多），并显著降低Bcl-2、c-Myc和突变型p53表达[4]。40μM的3-Bromopyruvic acid处理2小时能显著降低U118胶质母细胞瘤细胞活力，增加线粒体活性氧（ROS）生成[5]。100μM的3-Bromopyruvic acid处理12小时可诱导THP-1细胞DNA断裂，触发H2A.X磷酸化[6]。
在体内，胰腺癌小鼠模型经腹腔注射3-Bromopyruvic acid（20mg/kg；隔日一次；持续30天）后，肿瘤生长显著抑制、生存期延长，肿瘤组织中髓系抑制细胞数量减少且CD8+ T细胞浸润增加[7]。SW480细胞的异种移植瘤小鼠模型经腹腔注射3-Bromopyruvic acid（8mg/kg；每4天一次；持续28天）可显著抑制肿瘤进展，导致肿瘤组织血管分布紊乱、细胞核固缩及炎性细胞浸润[8]。