title: Enhanced antitumor activity of 3-bromopyruvate in combination with rapamycin in vivo and in vitro.
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.
authors: Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors: Qi
authors: Q
authors: Zhang
authors: Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors: Jing
authors: J
authors: Pan
authors: Chemoprevention Branch, National Cancer Institute, Bethesda, Maryland.
authors: Ronald A
authors: RA
authors: Lubet
authors: Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors: Steven M
authors: SM
authors: Komas
authors: Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors: Balaraman
authors: B
authors: Kalyanaraman
authors: Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors: Yian
authors: Y
authors: Wang
authors: Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin. myou@mcw.edu.
authors: Ming
authors: M
authors: You
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects*; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008805:Mice, Inbred A; D008928:Mitochondria / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D011773:Pyruvates / Q000494:pharmacology*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D011773:Pyruvates; C017092:bromopyruvate; D000255:Adenosine Triphosphate; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
references: Clin Cancer Res. 2008 Mar 15;14(6):1831-9
references: 18347186
references: Br J Cancer. 1993 Dec;68(6):1146-9
references: 8260366
references: Oncologist. 2008 Feb;13(2):139-47
references: 18305058
references: Clin Cancer Res. 2006 Jul 15;12(14 Pt 2):4446s-4450s
references: 16857826
references: Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4129-34
references: 21325052
references: Cancer Cell. 2005 Sep;8(3):179-83
references: 16169463
references: J Clin Oncol. 2013 Nov 20;31(33):4169-71
references: 24002497
references: Clin Cancer Res. 2004 Apr 1;10(7):2319-26
references: 15073107
references: Cancer Prev Res (Phila). 2009 Jun;2(6):531-7
references: 19470785
references: Br J Clin Pharmacol. 2003 Dec;56(6):588-99
references: 14616418
references: Int J Nanomedicine. 2008;3(2):133-49
references: 18686775
references: Neoplasia. 2007 May;9(5):401-5
references: 17534445
references: Mol Carcinog. 2011 Dec;50(12):913-21
references: 21374736
references: Clin Cancer Res. 2004 Sep 15;10(18 Pt 2):6382S-7S
references: 15448035
references: Leukemia. 2005 Dec;19(12):2153-8
references: 16193082
references: Crit Rev Oncol Hematol. 2007 Aug;63(2):172-82
references: 17540577
references: Cancer Prev Res (Phila). 2011 Feb;4(2):270-6
references: 21163938
references: Crit Rev Oncol Hematol. 2002 Jan;41(1):57-77
references: 11796232
references: Vet J. 2013 Jan;195(1):127-9
references: 22683393
references: Mol Cancer Ther. 2012 Jul;11(7):1510-7
references: 22532600
references: Neoplasia. 2006 Jan;8(1):52-8
references: 16533426
references: Cancer Prev Res (Phila). 2012 May;5(5):717-25
references: 22401980
references: Clin Cancer Res. 2010 Dec 1;16(23):5900-7
references: 21045083
references: Cancer Discov. 2013 Jan;3(1):82-95
references: 23242809
references: N Engl J Med. 2011 Apr 28;364(17):1595-606
references: 21410393
references: J Clin Invest. 2013 Feb;123(2):767-81
references: 23321674
references: CA Cancer J Clin. 2011 Jul-Aug;61(4):212-36
references: 21685461
references: Cancer Prev Res (Phila). 2010 Sep;3(9):1066-76
references: 20810672
references: Nat Rev Cancer. 2009 Jul;9(7):476-88
references: 19550424