Aerosolized 3-bromopyruvate inhibits lung tumorigenesis without causing liver toxicity. Cancer Prev Res (Phila) 2012 May;5(5):717-25
Date
03/10/2012Pubmed ID
22401980DOI
10.1158/1940-6207.CAPR-11-0338Scopus ID
2-s2.0-84866260153 (requires institutional sign-in at Scopus site) 35 CitationsAbstract
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.
Author List
Zhang Q, Pan J, North PE, Yang S, Lubet RA, Wang Y, You MAuthor
Paula E. North MD, PhD Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdenocarcinomaAdministration, Inhalation
Aerosols
Animals
Antineoplastic Agents
Cell Line, Tumor
Cell Survival
Chemical and Drug Induced Liver Injury
Down-Regulation
Drug Evaluation, Preclinical
Female
Humans
Lung Neoplasms
Mice
Models, Biological
Pyruvates