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PMID: 20438634 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

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

Molecular cancer ·Vol. 9 ·2010-05-03 ·Pages 99

Suttana W, Mankhetkorn S, Poompimon W, Palagani A, Zhokhov S, Gerlo S, Haegeman G, Berghe WV

Abstract

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 NFkappaB, 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 NFkappaB, which regulates inflammation, cell survival and P-gp expression and suppresses the apoptotic potential of chemotherapeutic agents. As such, NFkappaB inhibitors may promote apoptosis in cancer cells and could be used to overcome resistance to chemotherapeutic agents. Although the natural withanolide withaferin A and polyphenol quercetin, show comparable inhibition of NFkappaB 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. This demonstrates that different classes of natural NFkappaB inhibitors can show different chemosensitizing effects in P-gp overexpressing cancer cells with impaired caspase activation and attenuated apoptosis.

MeSH Terms
ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis,genetics Animals Antineoplastic Agents/pharmacology Apoptosis/drug effects,genetics Blotting, Western Caspases/metabolism Cell Line, Tumor Drug Resistance, Neoplasm/drug effects,genetics Electrophoretic Mobility Shift Assay Enzyme Activation/drug effects,genetics Enzyme Inhibitors/pharmacology Enzyme-Linked Immunosorbent Assay Ergosterol/analogs & derivatives,pharmacology Flavonoids/pharmacology Gene Expression Gene Expression Regulation, Neoplastic/drug effects,genetics Humans Interleukin-6/biosynthesis K562 Cells Mice NF-kappa B/antagonists & inhibitors Phenols/pharmacology Polyphenols Quercetin/analogs & derivatives,pharmacology Reverse Transcriptase Polymerase Chain Reaction Withanolides
Chemicals
ATP Binding Cassette Transporter, Subfamily B, Member 1 Antineoplastic Agents Enzyme Inhibitors Flavonoids Interleukin-6 NF-kappa B Phenols Polyphenols Siamois 1 Siamois 2 Withanolides Quercetin Caspases withaferin A Ergosterol
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Suttana Wipob
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, Chiang Mai, Thailand.
Mankhetkorn Samlee
Poompimon Wilart
Palagani Ajay
Zhokhov Sergey
Gerlo Sarah
Haegeman Guy
Berghe Wim Vanden
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Article Info
Journal
Molecular cancer
Abbr.
Mol Cancer
ISSN
1476-4598
DOI
10.1186/1476-4598-9-99
Published
2010-05-03
Epub
2010-00-03
Pages
99
Language
English
Region
England
NLM ID
101147698
PMCID
PMC2873443
Subset
IM
External Links
PubMed source DOI: 10.1186/1476-4598-9-99 PMC Full Text View journal details
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