Antitumor activity of efrapeptins,alone or in combination with 2-deoxyglucose,in breast cancer in vitro and in vivo |
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Authors: | Adonia E. Papathanassiu Nicholas J. MacDonald David R. Emlet Hong A. Vu |
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Affiliation: | (1) Ergon Pharmaceuticals LLC, PO Box 1001, Silver Spring, MD 20910, USA;(2) Laboratory of Cancer Cell Biology and Genetics, Drexel University College of Medicine and the Allegheny-Singer Research Institute, Allegheny General Hospital, 10ST, 320 East North Avenue, Pittsburgh, PA 15212, USA;(3) Present address: Laboratory of Malaria Immunology and Vaccinology, Twinbrook I, Rm 1123, 5840 Fishers Ln, Rockville, MD 20852, USA;(4) Present address: Integrated BioTherapeutics, Inc., 20358 Seneca Meadows Parkway, Germantown, MD 20876, USA;(5) Present address: HHC, 28th Combat Aviation Brigade, 28th Infantry Division, Pennsylvania Army National Guard, BLDG 19-119, FTIG, Annville, PA 17003, USA |
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Abstract: | Efrapeptins (EF), a family of fungal peptides, inhibit proteasomal enzymatic activities and the in vitro and in vivo growth of HT-29 cells. They are also known inhibitors of F1F0-ATPase, a mitochondrial enzyme that functions as an Hsp90 co-chaperone. We have previously shown that treatment of cancer cells with EF results in disruption of the Hsp90:F1F0-ATPase complex and inhibition of Hsp90 chaperone activity. The present study examines the effect of EF on breast cancer growth in vitro and in vivo. As a monotherapy, EF inhibited cell proliferation in vitro with an IC50 value ranging from 6 nM to 3.4 μM. Inhibition of Hsp90 chaperone function appeared to be the dominant mechanism of action and the factor determining cellular sensitivity to EF. In vitro inhibition of proteasome became prominent in the absence of adequate levels of Hsp90 and F1F0-ATPase as in the case of the relatively EF-resistant MDA-MB-231 cell line. In vivo, EF inhibited MCF-7 and MDA-MB-231 xenograft growth with a maximal inhibition of 60% after administration of 0.15 and 0.3 mg/kg EF, respectively. 2-Deoxyglucose (2DG), a known inhibitor of glycolysis, acted synergistically with EF in vitro and antagonistically in vivo. In vitro, the synergistic effect was attributed to a prolonged endoplasmic reticulum (ER) stress. In vivo, the antagonistic effect was ascribed to the downregulation of tumoral and/or stromal F1F0-ATPase by 2DG. |
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Keywords: | Proteasome Hsp90 F1F0-ATPase Efrapeptin 2-Deoxyglucose |
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