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

Wipob Suttana UGent, Samlee Mankhetkorn, Wilart Poompimon, Ajay Palagani, Sergey Zhokhov UGent, Sarah Gerlo UGent, Guy Haegeman UGent and Wim Vanden Berghe UGent (2010) MOLECULAR CANCER. 9.
abstract
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 NF-kappa B, 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 NF-kappa B, which regulates inflammation, cell survival and P-gp expression and suppresses the apoptotic potential of chemotherapeutic agents. As such, NF-kappa B 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 NF-kappa B 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 NF kappa B inhibitors can show different chemosensitizing effects in P-gp overexpressing cancer cells with impaired caspase activation and attenuated apoptosis.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
MOLECULAR-MECHANISMS, INHIBITS PROLIFERATION, BLACK TEA POLYPHENOLS, NF-KAPPA-B, CASPASE-DEPENDENT APOPTOSIS, MULTIDRUG-RESISTANCE GENE, DRUG-RESISTANCE, TUMOR-CELLS, NECROSIS-FACTOR-ALPHA, BREAST-CANCER CELLS
journal title
MOLECULAR CANCER
Mol. Cancer
volume
9
article_number
99
pages
22 pages
Web of Science type
Article
Web of Science id
000278311600001
JCR category
ONCOLOGY
JCR impact factor
3.779 (2010)
JCR rank
54/181 (2010)
JCR quartile
2 (2010)
ISSN
1476-4598
DOI
10.1186/1476-4598-9-99
language
English
UGent publication?
yes
classification
A1
copyright statement
I have retained and own the full copyright for this publication
id
970302
handle
http://hdl.handle.net/1854/LU-970302
date created
2010-06-06 11:41:53
date last changed
2010-08-09 12:10:05
@article{970302,
  abstract     = {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 NF-kappa B, 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 NF-kappa B, which regulates inflammation, cell survival and P-gp expression and suppresses the apoptotic potential of chemotherapeutic agents. As such, NF-kappa B 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 NF-kappa B 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 NF kappa B inhibitors can show different chemosensitizing effects in P-gp overexpressing cancer cells with impaired caspase activation and attenuated apoptosis.},
  articleno    = {99},
  author       = {Suttana, Wipob and Mankhetkorn, Samlee and Poompimon, Wilart and Palagani, Ajay and Zhokhov, Sergey and Gerlo, Sarah and Haegeman, Guy and Vanden Berghe, Wim},
  issn         = {1476-4598},
  journal      = {MOLECULAR CANCER},
  keyword      = {MOLECULAR-MECHANISMS,INHIBITS PROLIFERATION,BLACK TEA POLYPHENOLS,NF-KAPPA-B,CASPASE-DEPENDENT APOPTOSIS,MULTIDRUG-RESISTANCE GENE,DRUG-RESISTANCE,TUMOR-CELLS,NECROSIS-FACTOR-ALPHA,BREAST-CANCER CELLS},
  language     = {eng},
  pages        = {22},
  title        = {Differential chemosensitization of P-glycoprotein overexpressing K562/Adr cells by withaferin A and Siamois polyphenols},
  url          = {http://dx.doi.org/10.1186/1476-4598-9-99},
  volume       = {9},
  year         = {2010},
}

Chicago
Suttana, Wipob, Samlee Mankhetkorn, Wilart Poompimon, Ajay Palagani, Sergey Zhokhov, Sarah Gerlo, Guy Haegeman, and Wim Vanden Berghe. 2010. “Differential Chemosensitization of P-glycoprotein Overexpressing K562/Adr Cells by Withaferin A and Siamois Polyphenols.” Molecular Cancer 9.
APA
Suttana, W., Mankhetkorn, S., Poompimon, W., Palagani, A., Zhokhov, S., Gerlo, S., Haegeman, G., et al. (2010). Differential chemosensitization of P-glycoprotein overexpressing K562/Adr cells by withaferin A and Siamois polyphenols. MOLECULAR CANCER, 9.
Vancouver
1.
Suttana W, Mankhetkorn S, Poompimon W, Palagani A, Zhokhov S, Gerlo S, et al. Differential chemosensitization of P-glycoprotein overexpressing K562/Adr cells by withaferin A and Siamois polyphenols. MOLECULAR CANCER. 2010;9.
MLA
Suttana, Wipob, Samlee Mankhetkorn, Wilart Poompimon, et al. “Differential Chemosensitization of P-glycoprotein Overexpressing K562/Adr Cells by Withaferin A and Siamois Polyphenols.” MOLECULAR CANCER 9 (2010): n. pag. Print.