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

Background: Multidrug 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...

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Main Authors: Wipob Suttana, Samlee Mankhetkorn, Wilart Poompimon, Ajay Palagani, Sergey Zhokhov, Sarah Gerlo, Guy Haegeman, Wim V. Berghe
Format: Journal
Published: 2018
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spelling th-cmuir.6653943832-505712018-09-04T04:51:14Z Differential chemosensitization of P-glycoprotein overexpressing K562/Adr cells by withaferin A and Siamois polyphenols Wipob Suttana Samlee Mankhetkorn Wilart Poompimon Ajay Palagani Sergey Zhokhov Sarah Gerlo Guy Haegeman Wim V. Berghe Biochemistry, Genetics and Molecular Biology Medicine Background: Multidrug 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.Results: Although 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.Conclusions: This 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. © 2010 Suttana et al; licensee BioMed Central Ltd. 2018-09-04T04:42:29Z 2018-09-04T04:42:29Z 2010-05-03 Journal 14764598 2-s2.0-77953552264 10.1186/1476-4598-9-99 https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=77953552264&origin=inward http://cmuir.cmu.ac.th/jspui/handle/6653943832/50571
institution Chiang Mai University
building Chiang Mai University Library
country Thailand
collection CMU Intellectual Repository
topic Biochemistry, Genetics and Molecular Biology
Medicine
spellingShingle Biochemistry, Genetics and Molecular Biology
Medicine
Wipob Suttana
Samlee Mankhetkorn
Wilart Poompimon
Ajay Palagani
Sergey Zhokhov
Sarah Gerlo
Guy Haegeman
Wim V. Berghe
Differential chemosensitization of P-glycoprotein overexpressing K562/Adr cells by withaferin A and Siamois polyphenols
description Background: Multidrug 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.Results: Although 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.Conclusions: This 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. © 2010 Suttana et al; licensee BioMed Central Ltd.
format Journal
author Wipob Suttana
Samlee Mankhetkorn
Wilart Poompimon
Ajay Palagani
Sergey Zhokhov
Sarah Gerlo
Guy Haegeman
Wim V. Berghe
author_facet Wipob Suttana
Samlee Mankhetkorn
Wilart Poompimon
Ajay Palagani
Sergey Zhokhov
Sarah Gerlo
Guy Haegeman
Wim V. Berghe
author_sort Wipob Suttana
title Differential chemosensitization of P-glycoprotein overexpressing K562/Adr cells by withaferin A and Siamois polyphenols
title_short Differential chemosensitization of P-glycoprotein overexpressing K562/Adr cells by withaferin A and Siamois polyphenols
title_full Differential chemosensitization of P-glycoprotein overexpressing K562/Adr cells by withaferin A and Siamois polyphenols
title_fullStr Differential chemosensitization of P-glycoprotein overexpressing K562/Adr cells by withaferin A and Siamois polyphenols
title_full_unstemmed Differential chemosensitization of P-glycoprotein overexpressing K562/Adr cells by withaferin A and Siamois polyphenols
title_sort differential chemosensitization of p-glycoprotein overexpressing k562/adr cells by withaferin a and siamois polyphenols
publishDate 2018
url https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=77953552264&origin=inward
http://cmuir.cmu.ac.th/jspui/handle/6653943832/50571
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