Abstract | INTRODUCTION: METHODS: We have recently synthesized a novel proteasome inhibitor (BU-32) and tested its growth inhibitory effects in different breast cancer cells including MCF-7, MDA-MB-231, and SKBR3 by in vitro cytotoxicity and proteasomal inhibition assays. The apoptotic potential of BU32 was tested using flow cytometry and analyzing cell cycle regulatory proteins. In vivo tumor xenograft studies for solid tumor as well as tumor metastasis were conducted using MDA-MB-231-GFP cells. RESULTS: We report for the first time that BU-32 exhibits strong cytotoxicity in a panel of cell lines: MDA-MB-231 (IC50 = 5.8 nM), SKBR3 (IC50 = 5.7 nM) and MCF-7 cells (IC50 = 5.8 nM). It downregulates a wide array of angiogenic marker genes and upregulates apoptotic markers, including Bid and Bax. Incubation of MDA-MB-231 cells with BU-32 results in the accumulation of cell cycle inhibitor proteins p21 and p27 and stabilization of the tumor suppressor protein p53. Studies in in vivo solid tumor and metastasis models show significant effect with a 0.06 mg/kg dose of BU-32 and marked reduction in tumor burden in the skeleton. CONCLUSIONS:
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Authors | Joseph K Agyin, Bindu Santhamma, Hareesh B Nair, Sudipa S Roy, Rajeshwar R Tekmal |
Journal | Breast cancer research : BCR
(Breast Cancer Res)
Vol. 11
Issue 5
Pg. R74
( 2009)
ISSN: 1465-542X [Electronic] England |
PMID | 19821999
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Boronic Acids
- NF-kappa B
- NSC D750499-S
- Protease Inhibitors
- Proteasome Inhibitors
- Pyrazines
- Pyrazoles
- Bortezomib
- Chymotrypsin
- Proteasome Endopeptidase Complex
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Topics |
- Animals
- Apoptosis
(drug effects)
- Bone Neoplasms
(drug therapy, enzymology, genetics, secondary)
- Boronic Acids
(pharmacology)
- Bortezomib
- Breast Neoplasms
(drug therapy, enzymology, genetics, pathology)
- Cell Growth Processes
(drug effects)
- Cell Line, Tumor
- Chymotrypsin
(antagonists & inhibitors, metabolism)
- Female
- Gene Expression Regulation, Neoplastic
(drug effects)
- Humans
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- NF-kappa B
(biosynthesis, genetics)
- Protease Inhibitors
(pharmacology)
- Proteasome Endopeptidase Complex
(metabolism)
- Proteasome Inhibitors
- Pyrazines
(pharmacology)
- Pyrazoles
(pharmacology)
- Xenograft Model Antitumor Assays
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