A perillyl alcohol-conjugated analog of 3-bromopyruvate without cellular uptake dependency on monocarboxylate transporter 1 and with activity in 3-BP-resistant tumor cells

Tumor Energy Metabolism and Potential of 3-Bromopyruvate as an Inhibitor of Aerobic Glycolysis: Implications in Tumor Treatment

“…Of note, GAPDH is S -nitrosylated by NO at the Cys150 residue, whether the Cys150 residue is at the same alkylating site of 3-BrPA? In 2017, Chen et al revealed that 3-BrPA caused rabbit GAPDH inactivation through the pyruvylation of four cysteine residues by mass spectrometry, especially for active site Cys150 residue (equivalent to Cys152 in human) [66]. We hypothesize that, similar to NO/GAPDH/Siah1 signaling cascade, 3-BrPA-mediated pyruvylation of GAPDH may promote the nuclear translocation of this protein and induce cell death via ubiquitination and degradation of nuclear proteins.…”

“…Additionally, GAPDH was found to be inhibited by 3-BrPA in several studies performed by different research groups (Figure 5) [64,65,66]. Using a radiolabeled [ 14 C]-3-BrPA, GAPDH was identified as the primary intracellular target of 3BrPA in multiple cancer cell lines via 2D gel electrophoretic autoradiography, mass spectrometry, and immunoprecipitation techniques [63].…”

“…Using a radiolabeled [ 14 C]-3-BrPA, GAPDH was identified as the primary intracellular target of 3BrPA in multiple cancer cell lines via 2D gel electrophoretic autoradiography, mass spectrometry, and immunoprecipitation techniques [63]. In addition, the pyruvylation of GAPDH by 3-BrPA led to functional loss of the enzyme in cells and in vitro and in vivo [62,63,66,67,68]. In HepG2 cells, a treatment with 0.15 mM 3-BrPA for 30 min caused more than 70% inhibition of GAPDH activity [62].…”

“…In HepG2 cells, a treatment with 0.15 mM 3-BrPA for 30 min caused more than 70% inhibition of GAPDH activity [62]. In human colorectal cancer HCT116 cells, GAPDH activity was seriously inhibited by 3-BrPA with an IC 50 value less than 30 μM [66]. A K i value of approximately 25 μM for this inhibition was determined in vitro [67].…”

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

“…Accordingly, topical administration of 3BP is not only proved to be a promising strategy for treatment of unresectable melanoma, but also reasoned that trials for testing the efficacy of topical 3BP are possibly warranted for other skin cancers. It is also a challenge for future studies to develop other strategies to deliver 3BP by a nanovehicle [36][37][38][39] or to develop more efficient derivatives [40][41][42]. Further studies will thus be required to clarify the adverse effects of 3-bromopyruvate on normal cells or tissues of various organs.…”