Key Role of Nuclear Factor-κB in the Cellular Pharmacokinetics of Adriamycin in MCF-7/Adr Cells: The Potential Mechanism for Synergy with 20(<i>S</i>)-Ginsenoside Rh2

Zhang, Jingwei; Meng, Ling; Zhou, Fang; Sun, Haopeng; Hao, Gang; Wu, Xiujie; Wang, Guangji

doi:10.1124/dmd.112.045187

Cited by 37 publications

(27 citation statements)

References 50 publications

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“…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.…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Cen

Zhang

Liu

et al. 2016

Oxidative Medicine and Cellular Longevity

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Reactive oxygen species (ROS) play an important role in multidrug resistance (MDR). This study aimed to investigate the effects of long-term ROS alteration on MDR in MCF-7 cells and to explore its underlying mechanism. Our study showed both long-term treatments of H2O2 and glutathione (GSH) led to MDR with suppressed iROS levels in MCF-7 cells. Moreover, the MDR cells induced by 0.1 μM H2O2 treatment for 20 weeks (MCF-7/ROS cells) had a higher viability and proliferative ability than the control MCF-7 cells. MCF-7/ROS cells also showed higher activity or content of intracellular antioxidants like glutathione peroxidase (GPx), GSH, superoxide dismutase (SOD), and catalase (CAT). Importantly, MCF-7/ROS cells were characterized by overexpression of MDR-related protein 1 (MRP1) and P-glycoprotein (P-gp), as well as their regulators NF-E2-related factor 2 (Nrf2), hypoxia-inducible factor 1 (HIF-1α), and the activation of PI3K/Akt pathway in upstream. Moreover, several typical MDR mediators, including glutathione S-transferase-π (GST-π) and c-Myc and Protein Kinase Cα (PKCα), were also found to be upregulated in MCF-7/ROS cells. Collectively, our results suggest that ROS may be critical in the generation of MDR, which may provide new insights into understanding of mechanisms of MDR.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Cen

Zhang

Liu

et al. 2016

Oxidative Medicine and Cellular Longevity

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“…It was reported that the MAPK/NF-κB pathway mediates doxorubicin-induced P-gp expression in MCF-7/ Adr cells and subsequently alters the cellular pharmacokinetics of doxorubicin (3). Paracrine signaling through the receptor activator of the NF-κB (RANK) pathway was reported to promote the development of mammary stem cells and breast cancer, and high levels of RANK were found in human primary breast adenocarcinomas that lack expression of the hormone receptors estrogen and progesterone (triple-negative breast adenocarcinomas) and in tumors with a high pathological grade and proliferation index; in addition, high RANK/RANKL expression was significantly associated with metastatic tumors.…”

Section: Discussionmentioning

confidence: 99%

“…NF-κB is reported to be involved in regulating the expression of MDR1 and CD44 genes in multiple cancer cells (3)(4)(5)(6)(7), and it has been found that the CD44-hyaluronan (HA) interaction induces ankyrin binding to P-gp, resulting in the efflux of chemotherapeutic drugs and development of MDR in cancer (8,9).…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin induces drug resistance and expression of the novel CD44st via NF-κB in human breast cancer MCF-7 cells

et al. 2014

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Abstract. CD44, a major receptor for hyaluronan (HA), is a member of a class of adhesion molecules of unknown classification involved in cell proliferation, differentiation, migration, angiogenesis, and the presentation of specific cytokines to the corresponding receptors as well as in cell signaling transduction. It has recently been discovered that CD44, a marker of tumor stem cells, is involved in the drug resistance and invasion of multiple types of tumors. The 20 exons in the CD44 gene that are alternatively spliced, give rise to many CD44 isoforms, possibly including tumor-specific sequences. Dozens of CD44 isoforms have been found, to date, and the standard CD44 (CD44s) isoform is the most common. We recently showed that a novel short-tail isoform of CD44 (CD44st) was expressed in multidrug-resistant human breast cancer MCF-7/Adr cells. Moreover, the novel CD44st was able to interact with HA and regulate the expression of matrix metalloproteinase (MMP)-2 and MMP-9, which increased the invasive capability of MCF-7 cells through the Ras/MAPK signaling pathway. In the present study, we verified that MCF-7 cells subjected to drug pressure develop multidrug resistance to doxorubicin, and the expression levels of multidrug resistance protein 1 (MDR1), CD44st and nuclear factor-κB (NF-κB) mRNA and protein were gradually upregulated in a dose-dependent manner in MCF-7 cells treated with doxorubicin. HA increases the secretion of MMP-2 and MMP-9 in multidrug-resistant MCF-7 cells and affected the invasive ability of MCF-7 cells through the upregulation of CD44st expression, and such an effect was blocked by the NF-κB-specific inhibitor BMS-345541.

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“…Currently, the exact signaling pathways and targets mediating the antitumor properties of G-Rh2 in lung cancer have yet to be elucidated (Zhang et al, 2012;An et al, 2013;Kim et al, 2014). This study investigates the molecular pathways associated with G-Rh2 that regulate cell proliferation inhibition and apoptosis induction in the human lung cancer cell line A549.…”

Section: Introductionmentioning

confidence: 99%

JNK pathway and relative transcriptional factor were involved in ginsenoside Rh2-mediated G1 growth arrest and apoptosis in human lung adenocarcinoma A549 cells

et al. 2016

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ABSTRACT. Ginsenoside Rh2 has been shown to have an antitumor effect on a wide range of cancers. A previous study has shown that ginsenoside Rh2 can inhibit the proliferation of the human lung adenocarcinoma A549 cell line in a dose-dependent manner by activating caspase-8/3 activity to promote apoptosis. However, the association of the JNK signaling pathways and transcription factors with ginsenoside Rh2 in the suppression of non-small cell lung cancer has not yet been reported. In this study, we found that ginsenoside Rh2 can activate the JNK/MAPKs signaling pathway and increase the phosphorylation and transcriptional activity of the transcription factors AP-1 and ATF2. Ginsenoside Rh2 also reduced the expression of transcription factors E2F1 and c-Myc. Furthermore, ginsenoside Rh2 affected the expression levels of cyclin D1 and the CDK4 protein, which are key regulatory factors of the G1/S cyclin-dependent kinase. The anti-proliferative and induced apoptotic effects of ginsenoside Rh2 on A549 cell provide evidence to support the application of traditional Chinese medicine to lung cancer treatment.

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Key Role of Nuclear Factor-κB in the Cellular Pharmacokinetics of Adriamycin in MCF-7/Adr Cells: The Potential Mechanism for Synergy with 20(S)-Ginsenoside Rh2

Cited by 37 publications

References 50 publications

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

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

Doxorubicin induces drug resistance and expression of the novel CD44st via NF-κB in human breast cancer MCF-7 cells

JNK pathway and relative transcriptional factor were involved in ginsenoside Rh2-mediated G1 growth arrest and apoptosis in human lung adenocarcinoma A549 cells

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