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.

Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication

“…However, in a case study performed in Egypt, the killing effect of 3-BP was not as potent as expected in the treatment of a 28-year-old man who presented with stage Ⅳ metastatic melanoma. The patient died of cancer progression even though he had received 3-BP treatment [3] . Based on the cancer progression despite 3-BP treatment in this case, mechanisms beyond the Warburg effect may contribute to cancer cell survival, i.e., evading the glycolytic pathway or attenuating the 3-BP anticancer effect.…”

Effect of 3-Bromopyruvate and Atovaquone on Infection during In Vitro Interaction of Toxoplasma gondii and LLC-MK2 Cells

“…The enzyme hexokinase II was the first reported target of 3-BrPA (12), but this alkylating agent selectively inhibits mitochondrial oxidative phosphorylation, angiogenesis, and energy production in cancer cells (13,14). The enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is also inhibited by 3-BrPA in human hepatocellular carcinoma cell lines (15), leading to death by apoptosis (16).…”

3‐Bromopyruvate as a potent anticancer therapy in honor and memory of the late Professor André Goffeau

“…The ATP deficit due to the action of 3 BP prevents full operation of the efflux pumps, which are not able to pump out of the cells large quantities of the following agents: cisplatin, doxorubicin, 5‐fluorouracil, paclitaxel, epirubicin, daunorubicin, and mitoxantrone (Rello et al, ; Sánchez‐Aragó & Cuezva, ; Wu et al, ). Moreover, previous studies showed that 3 BP acts synergistically with compounds, which are GSH‐depleting agents such as buthionine sulfoximine, methionine sulfoximine, and acetaminophen (El Sayed et al, ; El Sayed, Baghdadi, Almaramhy, Ayat, & Donki, ; Garbutcheon‐Singh, Harper, & Aldrich‐Wright, ; Lee et al, ; Lis, Dyląg, et al, ; Majkowska‐Skrobek et al, ; Niedźwiecka et al, ). Drugs used in the treatment of MM cause accumulation of toxicity in organisms and consequently numerous side effects (Benboubker et al, ).…”