Aerosolized 3-bromopyruvate inhibits lung tumorigenesis without causing liver toxicity.

Abstract

3-Bromopyruvate, an alkylating agent and a well-known inhibitor of energy metabolism, has been proposed as a specific anticancer agent. However, the chemopreventive effect of 3-bromopyruvate in lung tumorigenesis has not been tested. In this study, we investigated the chemopreventive activity of 3-bromopyruvate in a mouse lung tumor model. Benzo(a)pyrene was used to induce lung tumors, and 3-bromopyruvate was administered by oral gavage to female A/J mice. We found that 3-bromopyruvate significantly decreased tumor multiplicity and tumor load by 58% and 83%, respectively, at a dose of 20 mg/kg body weight by gavage. Due to the known liver toxicity of 3-bromopyruvate in animal models given large doses of 3-bromopyruvate, confirmed in this study, we decided to test the chemopreventive activity of aerosolized 3-bromopyruvate in the same lung tumor model. As expected, aerosolized 3-bromopyruvate similarly significantly decreased tumor multiplicity and tumor load by 49% and 80%, respectively, at a dose of 10 mg/mL by inhalation. Interestingly, the efficacy of aerosolized 3-bromopyruvate did not accompany any liver toxicity indicating that it is a safer route of administering this compound. Treatment with 3-bromopyruvate increased immunohistochemical staining for cleaved caspase-3, suggesting that the lung tumor inhibitory effects of 3-bromopyruvate were through induction of apoptosis. 3-Bromopyruvate also dissociated hexokinase II from mitochondria, reduced hexokinase activity, and blocked energy metabolism in cancer cells, finally triggered cancer cell death and induced apoptosis through caspase-3, and PARP in human lung cancer cell line. The ability of 3-bromopyruvate to inhibit mouse lung tumorigenesis, in part through induction of apoptosis, merits further investigation of this compound as a chemopreventive agent for human lung cancer.

• Authors: Qi Zhang, Jing Pan, Paula E North, Shoua Yang, Ronald A Lubet, Yian Wang, Ming You
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 5 Issue 5 Pg. 717-25 (May 2012) ISSN: 1940-6215 [Electronic] United States
• PMID: 22401980 (Publication Type: Journal Article)

Chemical References

• Aerosols
• Antineoplastic Agents
• Pyruvates
• bromopyruvate

Topics

• Adenocarcinoma (drug therapy, epidemiology, pathology)
• Adenocarcinoma of Lung
• Administration, Inhalation
• Aerosols
• Animals
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Chemical and Drug Induced Liver Injury (epidemiology, pathology)
• Down-Regulation (drug effects)
• Drug Evaluation, Preclinical
• Female
• Humans
• Lung Neoplasms (drug therapy, epidemiology, pathology)
• Mice
• Models, Biological
• Pyruvates (administration & dosage, adverse effects, pharmacology)