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

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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.
Keywords
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

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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 et al. “Differential Chemosensitization of P-glycoprotein Overexpressing K562/Adr Cells by Withaferin A and Siamois Polyphenols.” MOLECULAR CANCER 9 (2010): n. pag. Print.
@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},
  keywords     = {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},
}

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