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

Abstract

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.

Long‐Term Alteration of Reactive Oxygen Species Led to Multidrug Resistance in MCF‐7 Cells

“…In order to further elucidate the underlying mechanisms of ROS-induced MDR, immunofluorescence staining was performed to examine several transcriptional factors in close relationship with oxidative stress, including Nrf2, NF- κ B-p65, and HIF-1 α , which were also widely reported as regulators of efflux transporter like P-gp and MRP1 [21–24]. Our results showed that Nrf2, NF- κ B-p65, and HIF-1 α were found to be highly expressed in MCF-7/ROS cells compared to control MCF-7 cells.…”

“…Firstly, overexpressions of functional P-gp and MRP1, which are classic efflux mechanisms of anticancer drugs and correlate broadly with negative treatment response [44], were found in MCF-7 cells after long-term treatment with both H 2 O 2 and GSH. Secondly, the transcriptional factors of efflux transporter, such as Nrf2, NF- κ B, and HIF-1 α [21–24], were also upregulated in MCF-7/ROS cells. Importantly, the elevated levels of Nrf2 and HIF-1 α were mainly localized in the nuclei of MCF-7/ROS cells, which suggested them in activation.…”

Quercetin Iron (III) Complex Enhances Radiation-Induced Cell Death in Human Erythroleukemic Cell Lines by Increasing the Generation of Intracellular ROS

“…Thus, the strategy of using an ROS-generating agent to enhance cytotoxicity may not be generally applied to all cases. For resistant cells with a high antioxidant capacity, such strategies enhance cell survival and impair cellular responses to anticancer therapy (Suttana et al, 2010: Ding et al, 2015. Molecular event triggers in these cells require further study to better understand the mechanism underlying the effect of IronQ, although the present study provides preliminary experimental evidence of the efficiency of IronQ to sensitize cancer cells to radiotherapy.…”

Phytochemicals and Cancer Chemoprevention: Epigenetic Friends or Foe?

“…Also, chronic exposure to chemotherapeutic agents may epigenetically reprogram cancer cell metabolism and gene expression and trigger chemoresistance (Blair et al, 2011;Kujjo et al, 2011;S. V. Sharma et al, 2010;W. Suttana et al, 2010).…”

“…Iliopoulos et al, 2009;S. Maeda et al, 2009;Min et al, 2010;Naugler & Karin, 2008;W. Suttana et al, 2010;Yu et al, 2009).…”