Differential chemosensitization of P-glycoprotein overexpressing K562/Adr cells by withaferin A and Siamois polyphenols

Molecular Cancer

Research

Sergey Zhokhov¹  Ajay Palagani¹  Sarah Gerlo¹  Guy Haegeman¹  Wim Vanden Berghe²  Wilart Poompimon³  Samlee Mankhetkorn⁴  Wipob Suttana⁵ 

[1] Laboratory of Eukaryotic Gene Expression and Signal Transduction (LEGEST), Department of Physiology, Ghent University, K.L.Ledeganckstraat 35, Gent, Belgium;Laboratory of Eukaryotic Gene Expression and Signal Transduction (LEGEST), Department of Physiology, Ghent University, K.L.Ledeganckstraat 35, Gent, Belgium;Lab Protein Science, Proteomics and Epigenetic Signaling, Department of Biomedical Sciences, University Antwerp, Campus Drie Eiken, Universiteitsplein 1, Wilrijk, Belgium;Laboratory of Natural Products, Department of Chemistry, Faculty of Science, Lampang Rajabhat University, Lampang, Thailand;Laboratory of Physical Chemistry, Molecular and Cellular Biology and Center of Excellence for Molecular Imaging, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, 50200, Chiang Mai, Thailand;Laboratory of Physical Chemistry, Molecular and Cellular Biology and Center of Excellence for Molecular Imaging, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, 50200, Chiang Mai, Thailand;Laboratory of Eukaryotic Gene Expression and Signal Transduction (LEGEST), Department of Physiology, Ghent University, K.L.Ledeganckstraat 35, Gent, Belgium;

关键词: Quercetin;    K562 Cell;    Kaempferol;    Electrophoretic Mobility Shift Assay;    PARP Cleavage;   

DOI  :  10.1186/1476-4598-9-99

 received in 2009-08-27, accepted in 2010-05-03,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundMultidrug resistance (MDR) is a major obstacle in cancer treatment and is often the result of overexpression of the drug efflux protein, P-glycoprotein (P-gp), as a consequence of hyperactivation of NFκB, AP1 and Nrf2 transcription factors. In addition to effluxing chemotherapeutic drugs, P-gp also plays a specific role in blocking caspase-dependent apoptotic pathways. One feature that cytotoxic treatments of cancer have in common is activation of the transcription factor NFκB, which regulates inflammation, cell survival and P-gp expression and suppresses the apoptotic potential of chemotherapeutic agents. As such, NFκB inhibitors may promote apoptosis in cancer cells and could be used to overcome resistance to chemotherapeutic agents.ResultsAlthough the natural withanolide withaferin A and polyphenol quercetin, show comparable inhibition of NFκB target genes (involved in inflammation, angiogenesis, cell cycle, metastasis, anti-apoptosis and multidrug resistance) in doxorubicin-sensitive K562 and -resistant K562/Adr cells, only withaferin A can overcome attenuated caspase activation and apoptosis in K562/Adr cells, whereas quercetin-dependent caspase activation and apoptosis is delayed only. Interestingly, although withaferin A and quercetin treatments both decrease intracellular protein levels of Bcl2, Bim and P-Bad, only withaferin A decreases protein levels of cytoskeletal tubulin, concomitantly with potent PARP cleavage, caspase 3 activation and apoptosis, at least in part via a direct thiol oxidation mechanism.ConclusionsThis demonstrates that different classes of natural NFκB inhibitors can show different chemosensitizing effects in P-gp overexpressing cancer cells with impaired caspase activation and attenuated apoptosis.

【 授权许可】

Unknown   
© Suttana et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.