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.
Acetaminophen ; therapeutic use ; Adult ; Carcinoma, Hepatocellular ; Disease Progression ; Drug Therapy, Combination ; Enzyme Inhibitors ; Glutathione ; Glycolysis ; Hexokinase ; Humans ; L-Lactate Dehydrogenase ; Lactic Acid ; Lung Neoplasms ; secondary ; Male ; Melanoma ; drug therapy ; Necrosis ; Neovascularization, Pathologic ; Pleural Neoplasms ; secondary ; Prognosis ; Pyruvates ; adverse effects ; therapeutic use ; Treatment Outcome

Objective: To study the antioxidant and anti-inflammatory activity of Butia capitata (B. capitata) leaf extracts along with phytochemical analysis of the proposed bioactive constituents. Methods: Different successive extracts of B. capitata Becc. leaves were prepared with selective organic solvents and screened for their anti-inflammatory activities in tested animals and in-vitro antioxidant effect. An extensive phytochemical investigation of the bioactive extracts through paper chromatography, thin layer chromatography, column chromatography, gas-liquid chromatography (GLC), high pressure liquid chromatography and spectral analysis. GC-Mass, ultraviolet, hydrogen and carbon nuclear magnetic resonance, electron ionization-mass spectrometry, heteronuclear multiple bond correlation and heteronuclear multiple quantum correlation were carried out. Results: Results showed that different extracts possess promising antioxidant effect and significant anti-inflammatory activity with variable degrees. The results of the phytochemical investigation of the bioactive extracts revealed the presence of volatile substances, lipoidal matter, α-tocopherol, free sugars, polysaccharides and flavonoidal compounds. Conclusions: B. capitata leaf extracts were shown to possess variable antioxidant effect, the most promising was methanol extract. Both polar and non polar extracts were proved to have anti-inflammatory activity, the non polar extract was superior in this respect. The bioactivity of the extracts was ascribed to the presence of flavonoids, sterols and a-tocopherol.

OBJECTIVETo study the antioxidant and anti-inflammatory activity of Butia capitata (B. capitata) leaf extracts along with phytochemical analysis of the proposed bioactive constituents.

METHODSDifferent successive extracts of B. capitata Becc. leaves were prepared with selective organic solvents and screened for their anti-inflammatory activities in tested animals and in-vitro antioxidant effect. An extensive phytochemical investigation of the bioactive extracts through paper chromatography, thin layer chromatography, column chromatography, gas-liquid chromatography (GLC), high pressure liquid chromatography and spectral analysis. GC-Mass, ultraviolet, hydrogen and carbon nuclear magnetic resonance, electron ionization-mass spectrometry, heteronuclear multiple bond correlation and heteronuclear multiple quantum correlation were carried out.

RESULTSResults showed that different extracts possess promising antioxidant effect and significant anti-inflammatory activity with variable degrees. The results of the phytochemical investigation of the bioactive extracts revealed the presence of volatile substances, lipoidal matter, α-tocopherol, free sugars, polysaccharides and flavonoidal compounds.

CONCLUSIONSB. capitata leaf extracts were shown to possess variable antioxidant effect, the most promising was methanol extract. Both polar and non polar extracts were proved to have anti-inflammatory activity, the non polar extract was superior in this respect. The bioactivity of the extracts was ascribed to the presence of flavonoids, sterols and α-tocopherol.