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

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 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.

• Authors: Wipob Suttana, Samlee Mankhetkorn, Wilart Poompimon, Ajay Palagani, Sergey Zhokhov, Sarah Gerlo, Guy Haegeman, Wim Vanden Berghe
• Journal: Molecular cancer (Mol Cancer) Vol. 9 Pg. 99 (May 03 2010) ISSN: 1476-4598 [Electronic] England
• PMID: 20438634 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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