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 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.


RESULTS
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.


CONCLUSIONS
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.
Suttana
Wipob
W
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
S
Poompimon
Wilart
W
Palagani
Ajay
A
Zhokhov
Sergey
S
Gerlo
Sarah
S
Haegeman
Guy
G
Berghe
Wim Vanden
WV
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D004875:Ergosterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D020014:K562 Cells; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010636:Phenols / Q000494:pharmacology; D059808:Polyphenols; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054358:Withanolides
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D015850:Interleukin-6; D016328:NF-kappa B; D010636:Phenols; D059808:Polyphenols; C521759:Siamois 1; C521760:Siamois 2; D054358:Withanolides; D011794:Quercetin; D020169:Caspases; C009684:withaferin A; D004875:Ergosterol