title: Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study.
abstract: 3-Bromopyruvate (3BP) is a new, promising anticancer alkylating agent with several notable functions. In addition to inhibiting key glycolysis enzymes including hexokinase II and lactate dehydrogenase (LDH), 3BP also selectively inhibits mitochondrial oxidative phosphorylation, angiogenesis, and energy production in cancer cells. Moreover, 3BP induces hydrogen peroxide generation in cancer cells (oxidative stress effect) and competes with the LDH substrates pyruvate and lactate. There is only one published human clinical study showing that 3BP was effective in treating fibrolamellar hepatocellular carcinoma. LDH is a good measure for tumor evaluation and predicts the outcome of treatment better than the presence of a residual tumor mass. According to the Warburg effect, LDH is responsible for lactate synthesis, which facilitates cancer cell survival, progression, aggressiveness, metastasis, and angiogenesis. Lactate produced through LDH activity fuels aerobic cell populations inside tumors via metabolic symbiosis. In melanoma, the most deadly skin cancer, 3BP induced necrotic cell death in sensitive cells, whereas high glutathione (GSH) content made other melanoma cells resistant to 3BP. Concurrent use of a GSH depletor with 3BP killed resistant melanoma cells. Survival of melanoma patients was inversely associated with high serum LDH levels, which was reported to be highly predictive of melanoma treatment in randomized clinical trials. Here, we report a 28-year-old man presented with stage IV metastatic melanoma affecting the back, left pleura, and lung. The disease caused total destruction of the left lung and a high serum LDH level (4,283 U/L). After ethics committee approval and written patient consent, the patient received 3BP intravenous infusions (1-2.2 mg/kg), but the anticancer effect was minimal as indicated by a high serum LDH level. This may have been due to high tumor GSH content. On combining oral paracetamol, which depletes tumor GSH, with 3BP treatment, serum LDH level dropped maximally. Although a slow intravenous infusion of 3BP appeared to have minimal cytotoxicity, its anticancer efficacy via this delivery method was low. This was possibly due to high tumor GSH content, which was increased after concurrent use of the GSH depletor paracetamol. If the anticancer effectiveness of 3BP is less than expected, the combination with paracetamol may be needed to sensitize cancer cells to 3BP-induced effects.
authors.affiliation: Department of Medical Oncology and Nuclear Medicine, Sohag Faculty of Medicine, Sohag University, Sohag, Egypt. salahfazara@yahoo.com, drsalahpediatr@yahoo.com.
authors.forename: Salah Mohamed
authors.initials: SM
authors.lastname: El Sayed
authors.forename: Walaa Gamal
authors.initials: WG
authors.lastname: Mohamed
authors.forename: Minnat-Allah Hassan
authors.initials: MA
authors.lastname: Seddik
authors.forename: Al-Shimaa Ahmed
authors.initials: AS
authors.lastname: Ahmed
authors.forename: Asmaa Gamal
authors.initials: AG
authors.lastname: Mahmoud
authors.forename: Wael Hassan
authors.initials: WH
authors.lastname: Amer
authors.forename: Manal Mohamed
authors.initials: MM
authors.lastname: Helmy Nabo
authors.forename: Ahmed Roshdi
authors.initials: AR
authors.lastname: Hamed
authors.forename: Nagwa Sayed
authors.initials: NS
authors.lastname: Ahmed
authors.forename: Ali Abdel-Rahman
authors.initials: AA
authors.lastname: Abd-Allah
mesh_terms: D000082:Acetaminophen / Q000627:therapeutic use*; D000328:Adult; D006528:Carcinoma, Hepatocellular; D018450:Disease Progression; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors; D005978:Glutathione; D006019:Glycolysis; D006593:Hexokinase; D006801:Humans; D007770:L-Lactate Dehydrogenase; D019344:Lactic Acid; D008175:Lung Neoplasms / Q000556:secondary*; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D009336:Necrosis; D009389:Neovascularization, Pathologic; D010997:Pleural Neoplasms / Q000556:secondary*; D011379:Prognosis; D011773:Pyruvates / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D004791:Enzyme Inhibitors; D011773:Pyruvates; D019344:Lactic Acid; D000082:Acetaminophen; C017092:bromopyruvate; D007770:L-Lactate Dehydrogenase; D006593:Hexokinase; D005978:Glutathione