دورية أكاديمية
Enhanced antitumor activity of 3-bromopyruvate in combination with rapamycin in vivo and in vitro.
| العنوان: | Enhanced antitumor activity of 3-bromopyruvate in combination with rapamycin in vivo and in vitro. |
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| المؤلفون: | Zhang Q; Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin., Pan J; Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin., Lubet RA; Chemoprevention Branch, National Cancer Institute, Bethesda, Maryland., Komas SM; Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin., Kalyanaraman B; Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin., Wang Y; Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin., You M; 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. |
| المصدر: | Cancer prevention research (Philadelphia, Pa.) [Cancer Prev Res (Phila)] 2015 Apr; Vol. 8 (4), pp. 318-26. Date of Electronic Publication: 2015 Feb 02. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101479409 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1940-6215 (Electronic) Linking ISSN: 19406215 NLM ISO Abbreviation: Cancer Prev Res (Phila) Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research |
| مواضيع طبية MeSH: | Apoptosis/*drug effects , Carcinoma, Non-Small-Cell Lung/*drug therapy , Carcinoma, Non-Small-Cell Lung/*pathology , Cell Proliferation/*drug effects , Lung Neoplasms/*drug therapy , Pyruvates/*pharmacology , Sirolimus/*pharmacology, Adenosine Triphosphate/metabolism ; Animals ; Antibiotics, Antineoplastic/pharmacology ; Antineoplastic Combined Chemotherapy Protocols ; Blotting, Western ; Carcinoma, Non-Small-Cell Lung/metabolism ; Energy Metabolism/drug effects ; Enzyme Inhibitors/pharmacology ; Female ; Glycolysis/drug effects ; Humans ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Mice ; Mice, Inbred A ; Mitochondria/drug effects ; Oxygen Consumption/drug effects ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/metabolism ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays |
| مستخلص: | 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. (©2015 American Association for Cancer Research.) |
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| معلومات مُعتمدة: | R01 CA134433 United States CA NCI NIH HHS; N01CN201200013(7) United States CN NCI NIH HHS; R01CA139959 United States CA NCI NIH HHS; R01 CA175360 United States CA NCI NIH HHS; R01CA175360 United States CA NCI NIH HHS; R01 CA152810 United States CA NCI NIH HHS; R01 CA139959 United States CA NCI NIH HHS; N01CN201200015(1) United States CN NCI NIH HHS; R01CA134433 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Antibiotics, Antineoplastic) 0 (Enzyme Inhibitors) 0 (Pyruvates) 63JMV04GRK (bromopyruvate) 8L70Q75FXE (Adenosine Triphosphate) EC 2.7.1.1 (MTOR protein, human) EC 2.7.11.1 (TOR Serine-Threonine Kinases) W36ZG6FT64 (Sirolimus) |
| تواريخ الأحداث: | Date Created: 20150204 Date Completed: 20160121 Latest Revision: 20211203 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC6004825 |
| DOI: | 10.1158/1940-6207.CAPR-14-0142 |
| PMID: | 25644152 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1940-6215 |
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| DOI: | 10.1158/1940-6207.CAPR-14-0142 |