BackgroundMultidrug 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 NFκB, 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 NFκB, which regulates inflammation, cell survival and P-gp expression and suppresses the apoptotic potential of chemotherapeutic agents. As such, NFκB inhibitors may promote apoptosis in cancer cells and could be used to overcome resistance to chemotherapeutic agents.ResultsAlthough the natural withanolide withaferin A and polyphenol quercetin, show comparable inhibition of NFκB 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.ConclusionsThis demonstrates that different classes of natural NFκB inhibitors can show different chemosensitizing effects in P-gp overexpressing cancer cells with impaired caspase activation and attenuated apoptosis.
The objectives of this study were to investigate the behavior of flavonoids in an aqueous physiological buffer and to determine the structural and functional group substitution which is responsible for their anticancer action. The deprotonated anionic form of 7 flavonoids can easily be determined using spectrophotometry, and owing to its charged state, is highly soluble in aqueous physiological buffer and is not prone to aggregation. The protonated form of these 7 flavonoids is much less soluble and tends to aggregate following precipitation. For all flavonoids studied except catechin and 5,5 -dihydroxy-6,7,3 ,4 -tetramethoxyflavone, it was possible to determine the rates of deprotonation; pKa value of eriodictyol, apigenin, kaempferol, quercetin, WP 279, and WP 283 was equal to 7. 00, 8.72, 7.86, 8.30, 7.70 and 9.90, respectively. The methoxyl group substitutions in place of hydrogen atoms and/or hydroxyl groups at various positions of carbon atoms in ring A, B and C particularly WP 283 resulted in an increase in the solubility, lipophilicity, and specifically its anticancer efficacy (by 60-fold). The neutral forms of flavonoids are predominantly active molecules and the active sites responsible for anticancer activity are found in ring A and C, especially C4=O, C5-OH and C2=C3.
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