BAY 87‐2243, a highly potent and selective inhibitor of hypoxia‐induced gene activation has antitumor activities by inhibition of mitochondrial complex I

Cancer Medicine - Tập 2 Số 5 - Trang 611-624 - 2013
Peter Ellinghaus1, Iring Heisler1, Kerstin Unterschemmann1, Michael Haerter1, Hartmut Beck1, Susanne Greschat1, Alexander Ehrmann1, Holger Summer1, Ingo Flamme1, Felix Oehme1, Karl‐Heinz Thierauch2, Martin Michels1, Holger Hess‐Stumpp2, Karl Ziegelbauer2
1Bayer Pharma AG, Global Drug Discovery, Wuppertal, Germany
2Bayer Pharma AG, Global Drug Discovery, Berlin, Germany

Tóm tắt

AbstractThe activation of the transcription factor hypoxia‐inducible factor‐1 (HIF‐1) plays an essential role in tumor development, tumor progression, and resistance to chemo‐ and radiotherapy. In order to identify compounds targeting the HIF pathway, a small molecule library was screened using a luciferase‐driven HIF‐1 reporter cell line under hypoxia. The high‐throughput screening led to the identification of a class of aminoalkyl‐substituted compounds that inhibited hypoxia‐induced HIF‐1 target gene expression in human lung cancer cell lines at low nanomolar concentrations. Lead structure BAY 87‐2243 was found to inhibit HIF‐1α and HIF‐2α protein accumulation under hypoxic conditions in non‐small cell lung cancer (NSCLC) cell line H460 but had no effect on HIF‐1α protein levels induced by the hypoxia mimetics desferrioxamine or cobalt chloride. BAY 87‐2243 had no effect on HIF target gene expression levels in RCC4 cells lacking Von Hippel–Lindau (VHL) activity nor did the compound affect the activity of HIF prolyl hydroxylase‐2. Antitumor activity of BAY 87‐2243, suppression of HIF‐1α protein levels, and reduction of HIF‐1 target gene expression in vivo were demonstrated in a H460 xenograft model. BAY 87‐2243 did not inhibit cell proliferation under standard conditions. However under glucose depletion, a condition favoring mitochondrial ATP generation as energy source, BAY 87‐2243 inhibited cell proliferation in the nanomolar range. Further experiments revealed that BAY 87‐2243 inhibits mitochondrial complex I activity but has no effect on complex III activity. Interference with mitochondrial function to reduce hypoxia‐induced HIF‐1 activity in tumors might be an interesting therapeutic approach to overcome chemo‐ and radiotherapy‐resistance of hypoxic tumors.

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Tài liệu tham khảo

10.1007/978-1-4615-4863-8_70

10.1016/j.ccr.2004.06.009

10.1158/1535-7163.MCT-07-0463

10.1038/nm0603-677

Kwon H. C., 2010, Clinicopathological significance of p53, hypoxia‐inducible factor 1alpha, and vascular endothelial growth factor expression in colorectal cancer, Anticancer Res., 10, 4163

10.1007/BF02482169

10.1158/0008-5472.CAN-04-4426

10.1093/jnci/djh168

10.1073/pnas.0706585104

10.1111/j.1751-1097.1999.tb07997.x

10.1016/j.febslet.2006.10.008

10.1161/CIRCULATIONAHA.108.779751

10.1016/S0006-291X(02)00862-8

10.1152/physiolgenomics.00094.2011

10.1016/j.ab.2004.03.066

10.1038/mt.2008.90

10.1158/0008-5472.CAN-10-3838

10.1074/jbc.M504342200

10.1002/ijc.23075

10.1158/0008-5472.CAN-10-1075

10.1073/pnas.0909353106

10.1113/expphysiol.2006.033506

10.1016/j.cmet.2011.10.008

10.1038/nprot.2008.61

10.1074/jbc.M106363200

10.1016/S0005-2728(99)00051-1

10.1158/1535-7163.MCT-08-0510

10.1016/j.tips.2012.01.005

10.1002/ijc.23807

10.1158/0008-5472.CAN-04-2116

10.1074/jbc.M204733200

Zhong H., 2000, Modulation of hypoxia‐inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3‐kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics, Cancer Res., 60, 1541

10.1016/j.ejmech.2012.01.033

10.1016/j.cmet.2005.05.002

10.1016/j.brainres.2010.03.102

10.1016/j.bbrc.2012.08.042

10.1089/ars.2011.4078

10.1002/jcp.22788

10.1038/nrd3137

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Cancer Medicine

Tập 2 Số 5

611-624

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