Curcumin down-regulates the multidrug-resistance mdr1b gene by inhibiting the PI3K/Akt/NFκB pathway

Choi, Byeong Hyeok; Kim, Chang Gun; Lim, Yoongho; Shin, Soon Young; Lee, Young Han

doi:10.1016/j.canlet.2007.10.003

Cited by 197 publications

(140 citation statements)

References 24 publications

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“…In addition, MDR-1 gene expression is regulated by NF-kB in different cell types (Zhou and Kuo, 1997;Thevenod et al, 2000;Bentires-Alj et al, 2003), and several groups have shown that curcumin downregulates MDR-1 expression in different cell types either through inhibiting the NF-kB pathway or by direct interaction (Anuchapreeda et al, 2002;Choi et al, 2008;Hou et al, 2008;Ganta and Amiji, 2009). Our data suggest that the inhibition of MDR-1 expression by curcumin in 3-MC-induced tumor samples can enhance the intracellular accumulation of paclitaxel and contribute, at least in part, to the synergistic effect of these agents.…”

Section: Discussionmentioning

confidence: 99%

Molecular evidences for the chemosensitizing efficacy of liposomal curcumin in paclitaxel chemotherapy in mouse models of cervical cancer

et al. 2011

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The microtubule-targeting antineoplastic agent, paclitaxel, is highly efficacious against a wide spectrum of human cancers. However, dose-limiting toxicity and development of drug resistance limit its clinical application. Development of novel strategies that overcome chemoresistance and sensitize cancer cells to paclitaxel can enhance the therapeutic effect of this drug. We have previously shown that curcumin, a natural polyphenol, enhances paclitaxelinduced cytotoxicity in vitro through downregulation of nuclear factor (NF)-jB and Akt pathways. This study was undertaken to determine whether this synergism exists in vivo and to elucidate the underlying molecular mechanisms. Mouse cervical multistage squamous cell carcinoma model using 3-methylcholanthrene (3-MC) and a xenograft model of human cervical cancer in nonobese diabetic severe combined immunodeficient (NOD-SCID) mice using HeLa cells were used to evaluate the synergism. We observed that the combined treatment of curcumin and paclitaxel induced a synergestic reduction in the tumor incidence as well as tumor volume of animals compared with the individual treatments of paclitaxel or curcumin, although curcumin alone could not induce any significant effect at the concentration used. The results suggest that a suboptimal concentration of curcumin augments the antitumor action of paclitaxel by downregulating the activation and downstream signaling of antiapoptotic factors and survival signals such as NF-jB, Akt and mitogen-activated protein kinases that have significant roles in proliferation, survival, angiogenesis and metastasis. This study revealed for the first time that 3-MC-induced tumorigenesis in mice is associated with a strong constitutive activation of NF-jB activity. Furthermore, we also observed that pre-exposure of carcinoma cells isolated from 3-MC-induced tumors to curcumin potentiates paclitaxel-induced apoptosis. Overall, the findings of this preclinical study provide a strong rationale for the validation of this combination through clinical trials. As curcumin could effectively downregulate all these survival signals induced by paclitaxel, we suggest it as a potent chemosensitizer to improve the therapeutic index of paclitaxel.

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Section: Discussionmentioning

confidence: 99%

Molecular evidences for the chemosensitizing efficacy of liposomal curcumin in paclitaxel chemotherapy in mouse models of cervical cancer

et al. 2011

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“…Natural medicines have been widely used for anti-oxidative stress, anti-inflammation and reversal of multidrug resistance of tumor cells in recent years (15,19). Resveratrol has an excellent effect on anti-oxidative stress and anti-inflammation (24)(25)(26), and it has the potential to ameliorate local inflammation by suppressing tumor necrosis factor-α-induced interleukin-8 release (19,(24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

“…It is well known that P-gp expression is closely associated with the nuclear factor (NF)-κB signaling pathway (12), the mitogen-activated protein kinase (MAPK) signaling pathway (13), cylooxygenases-2 (14) and phosphoinositide 3-kinase (15). NF-κB can bind to the NF-κB binding sites in the MDR1 promoter region, which results in the activation of the transcription of the MDR1 gene (16).…”

Section: Introductionmentioning

confidence: 99%

Resveratrol reverses P-glycoprotein-mediated multidrug resistance of U2OS/ADR cells by suppressing the activation of the NF-κB and p38 MAPK signaling pathways

Zhang

et al. 2016

Oncology Letters

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Abstract. The present study aimed to investigate the reversal effect of resveratrol on the phenomenon of multidrug resistance in U2OS/adriamycin (ADR) cells and to clarify the molecular mechanisms. To examine the cell survival and half-inhibitory concentration (IC 50 ) of ADR in U2OS and U2OS/ADR cells, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used. The accumulation of ADR in U2OS and U2OS/ADR cells was investigated by flow cytometry. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to detect the expression of multidrug resistance protein 1 (MDR1), P-glycoprotein (P-gp), p65 and p38. Compared with U2OS cells, the IC 50 value of ADR was significantly increased in U2OS/ADR cells, which exhibited high levels of MDR1/P-gp. However, resveratrol could drastically reduce the IC 50 value of ADR and the expression of MDR1/P-gp, and increased the accumulation of ADR in U2OS/ADR cells. In addition, the expression levels of p38 (phosphorylated) and p65 (acetylated and total) in U2OS/ADR cells were also significantly suppressed by resveratrol. These results suggested that the nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK) signaling pathways are correlated with ADR-induced drug resistance in U2OS/ADR cells. Furthermore, resveratrol could downregulate the expression of MDR1/P-gp and reverse the drug resistance phenomenon in U2OS/ADR cells partly at least by suppressing the activation of the NF-κB and p38 MAPK signaling pathways.

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Section: Abstract Background/aim: (-)-Epigallocatechin-3-gallate (Egmentioning

confidence: 99%

“…We have previously suggested that the P-gp level was up-regulated through the activation of protein kinase C/nuclear factor-ĸB (PKC/NF-ĸB) in rats with streptozotocin-induced diabetes (8). Further, the expression of MDR1 gene has been also shown to be induced by PI3K/Akt/NF-ĸB signaling (9,10).EGCG has been shown to activate ERK and PI3K/Akt signaling and induce antioxidant enzymes in human mammary epithelial cells (11). Contrarily, it has been shown that EGCG inhibits the PI3K/Akt system in fibroblast cells (12) and the phosphorylation of ERK and Akt kinases in epidermal growth factor (EGF)-stimulated cells (13).…”

mentioning

confidence: 99%

(–)-Epigallocatechin-3-gallate Down-regulates Doxorubicin-induced Overexpression of P-glycoprotein Τhrough the Coordinate Inhibition of PI3K/Akt and MEK/ERK Signaling Pathways

Satonaka

Ishida

Takai

et al. 2017

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Abstract. Background/Aim: (-)-Epigallocatechin-3-gallate (EGCG) has been indicated to regulate the function of Pglycoprotein (P-gp), which is a drug transporter encoded by the MDR1 (ABCB1) gene. P-gp expression is induced by doxorubicin (DOX). We aimed to clarify the mechanisms and inhibitory effects of EGCG on DOX-induced P-gp expression in HepG2 cells. Materials and Methods: Rhodamine 123 (Rho123) was used for P-gp substrate. Western blotting and polymerase chain reactions (PCRs) were conducted using specific antibodies and primer sets. Results: The DOXpretreated cells accumulated a significantly decreased amount of Rho123), than control cells; however, the cells pretreated with EGCG and DOX, in combination, accumulated Rho123 more than DOX-pretreated cells. DOX induced the overexpression of MDR1 mRNA and increased the phosphorylation of Akt, ERK1/2, p38 MAPK and JNK. EGCG significantly inhibited the phosphorylation of Akt and ERK. The DOX-induced P-gp overexpression was partially suppressed by an inhibitor of MEK1/2 (U0126), but not by a PI3K inhibitor (LY294002). Interestingly, the expression of P-gp was synergistically inhibited by combined treatment of U0126 with LY294002 and also inhibited by an mTORC1 inhibitor, rapamycin. Conclusion: EGCG inhibited DOX-induced overexpression of P-gp through the coordinate inhibitory action on MEK/ERK and PI3K/Akt signaling pathways.(-)-Epigallocatechin gallate (EGCG) is the most abundant component of tea polyphenols having various profitable properties, including anti-oxidative activity and cancerpreventive effect (1). In addition, concerning antitumor drug resistance, EGCG has been shown to decrease doxorubicin (DOX) resistance in a human carcinoma xenograft model mice (2) and inhibit the transport function of P-glycoprotein (P-gp), an export drug transporter causing antitumor multidrug resistance (MDR) in tumor cells (3)(4)(5).Human P-gp is a plasma membrane protein of 170 kDa encoded by the MDR1 (ABCB1) gene. The expression of MDR1 gene and P-gp is affected by various chemical substances and physico-chemical stress (5-7). We have previously suggested that the P-gp level was up-regulated through the activation of protein kinase C/nuclear factor-ĸB (PKC/NF-ĸB) in rats with streptozotocin-induced diabetes (8). Further, the expression of MDR1 gene has been also shown to be induced by PI3K/Akt/NF-ĸB signaling (9,10).EGCG has been shown to activate ERK and PI3K/Akt signaling and induce antioxidant enzymes in human mammary epithelial cells (11). Contrarily, it has been shown that EGCG inhibits the PI3K/Akt system in fibroblast cells (12) and the phosphorylation of ERK and Akt kinases in epidermal growth factor (EGF)-stimulated cells (13). More recently, accumulating evidence indicates that EGCG can inhibit PI3K/Akt and MAPK signaling systems (14)(15)(16)(17).From these backgrounds, in the present study, we aimed to clarify whether EGCG could suppress MDR and inhibit the induction of P-gp overexpression by DOX through inhibition of PI3K/Akt and ERK/MAPK signal transduction s...

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Curcumin down-regulates the multidrug-resistance mdr1b gene by inhibiting the PI3K/Akt/NFκB pathway

Cited by 197 publications

References 24 publications

Molecular evidences for the chemosensitizing efficacy of liposomal curcumin in paclitaxel chemotherapy in mouse models of cervical cancer

Molecular evidences for the chemosensitizing efficacy of liposomal curcumin in paclitaxel chemotherapy in mouse models of cervical cancer

Resveratrol reverses P-glycoprotein-mediated multidrug resistance of U2OS/ADR cells by suppressing the activation of the NF-κB and p38 MAPK signaling pathways

(–)-Epigallocatechin-3-gallate Down-regulates Doxorubicin-induced Overexpression of P-glycoprotein Τhrough the Coordinate Inhibition of PI3K/Akt and MEK/ERK Signaling Pathways

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