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Enhanced antitumor activity of 3-bromopyruvate in combination with rapamycin in vivo and in vitro. Cancer Prev Res (Phila) 2015 Apr;8(4):318-26

Date

02/04/2015

Pubmed ID

25644152

Pubmed Central ID

PMC6004825

DOI

10.1158/1940-6207.CAPR-14-0142

Scopus ID

2-s2.0-84927674589 (requires institutional sign-in at Scopus site)   23 Citations

Abstract

3-Bromopyruvate (3-BrPA) is an alkylating agent and a well-known inhibitor of energy metabolism. Rapamycin is an inhibitor of the serine/threonine protein kinase mTOR. Both 3-BrPA and rapamycin show chemopreventive efficacy in mouse models of lung cancer. Aerosol delivery of therapeutic drugs for lung cancer has been reported to be an effective route of delivery with little systemic distribution in humans. In this study, 3-BrPA and rapamycin were evaluated in combination for their preventive effects against lung cancer in mice by aerosol treatment, revealing a synergistic ability as measured by tumor multiplicity and tumor load compared treatment with either single-agent alone. No evidence of liver toxicity was detected by monitoring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes. To understand the mechanism in vitro experiments were performed using human non-small cell lung cancer (NSCLC) cell lines. 3-BrPA and rapamycin also synergistically inhibited cell proliferation. Rapamycin alone blocked the mTOR signaling pathway, whereas 3-BrPA did not potentiate this effect. Given the known role of 3-BrPA as an inhibitor of glycolysis, we investigated mitochondrial bioenergetics changes in vitro in 3-BrPA-treated NSCLC cells. 3-BrPA significantly decreased glycolytic activity, which may be due to adenosine triphosphate (ATP) depletion and decreased expression of GAPDH. Our results demonstrate that rapamycin enhanced the antitumor efficacy of 3-BrPA, and that dual inhibition of mTOR signaling and glycolysis may be an effective therapeutic strategy for lung cancer chemoprevention.

Author List

Zhang Q, Pan J, Lubet RA, Komas SM, Kalyanaraman B, Wang Y, You M

Author

Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphate
Animals
Antibiotics, Antineoplastic
Antineoplastic Combined Chemotherapy Protocols
Apoptosis
Blotting, Western
Carcinoma, Non-Small-Cell Lung
Cell Proliferation
Energy Metabolism
Enzyme Inhibitors
Female
Glycolysis
Humans
Lung Neoplasms
Mice
Mice, Inbred A
Mitochondria
Oxygen Consumption
Pyruvates
Sirolimus
TOR Serine-Threonine Kinases
Tumor Cells, Cultured
Xenograft Model Antitumor Assays