Asclepiasterol, a novel C21 steroidal glycoside derived fromAsclepias curassavica, reverses tumor multidrug resistance by down-regulating P-glycoprotein expression

Yuan, Weiqi; Zhang, Rongrong; Wang, Jun; Ma, Yan; Li, Wenxue; Jiang, Ren Wang; Cai, Shaohui

doi:10.18632/oncotarget.8965

Cited by 27 publications

(18 citation statements)

References 60 publications

(57 reference statements)

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“…We further uncovered that US could increase ROS activity, but could not significantly decrease P-gp expression in these cells. Our results are similar to previous studies showing targeting P-gp was less effective in treating MCF-7 cells than that in treating MCF-7/ADR cells [ 55 , 56 ]. These probably result from the rather low baseline level of P-gp expression in drug-sensitive cells, which decreases the silence efficiency [ 56 ].…”

Section: Discussionsupporting

confidence: 92%

The effects of ultrasound exposure on P-glycoprotein-mediated multidrug resistance in vitro and in vivo

Huang

Huang²,

et al. 2018

J Exp Clin Cancer Res

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BackgroundMultidrug resistance (MDR) is often responsible for the failure of chemotherapy treatment, and current strategies for cancer MDR are not adequately satisfying as to their efficacy and safety. In this study, we sought to determine the anti-MDR effects of ultrasound (US) irradiation and its underlying mechanisms against drug-resistance.MethodsMDR variant MCF-7/ADR cell lines and endothelial cell lines were used to determine the appropriate ultrasound intensity for in vitro experiments. MCF-7/ADR cell and HEPG2/ADM cells were used to assess the anti-MDR effect of US irradiation. Intracellular adriamycin (ADM) accumulation, Cell viability, cell proliferation and cell apoptosis were evaluated after ADM + US treatment or ADM treatment alone. MCF-7/ADR xenograft mice were used to investigate the appropriate ultrasound intensity for in vivo experiments and its effect on the long-term prognosis. Underlining mechanisms by which ultrasound exposure reversing MDR phenotype were investigated both in vitro and in vivo.ResultsCombination of ADM and 0.74 W/cm2 US irradiation enhanced ADM intracellular concentration and nuclear accumulation in MCF-7/ADR and HEPG2/ADM cells, compared to those treated with ADM alone. Enhanced cellular ADM uptake and nuclei localization was associated with increased cytotoxicity of ADM to ADM-resistant cells, lower ADM-resistant cell viability and proliferative cell ratio, and higher apoptotic cell ratio. More importantly, US exposure increased the effectiveness of ADM to inhibit tumor growth in MCF-7/ADR xenograft mice. Mechanistically, US exposure promoted ADM accumulation in MDR cells mainly through down-regulation of P-glycoprotein (P-gp), which is dependent on US-induced intracellular reactive oxygen species (ROS) production. US-induced oxidative stress promoted miR-200c-3p and miR-34a-3p expression by forming miR-200c/34a/ZEB1 double-negative feedback loop. Finally, US-induced miR-200c/34a overexpression decreased P-gp expression and reversed MDR phenotype.ConclusionUS irradiation could reverse MDR phenotype by activating ROS-ZEB1-miR200c/34a-P-gp signal pathway. Our findings offer a new and promising strategy for sensitizing cells to combat MDR and to improve the therapeutic index of chemotherapy.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0900-6) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

The effects of ultrasound exposure on P-glycoprotein-mediated multidrug resistance in vitro and in vivo

Huang

Huang²,

et al. 2018

J Exp Clin Cancer Res

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“…However, little is known concerning the effects of TRIB2 gene knockdown on drug-resistant proteins. Previous studies have found that the downregulation of drug-resistance proteins may partly depend on inhibition of the ERK pathway in cancer (11)(12)(13). In the present study, we explored changes in the ERK signaling pathway after knockdown of the TRIB2 gene in K562/ADM cells.…”

Section: Introductionmentioning

confidence: 92%

TRIB2 knockdown as a regulator of chemotherapy resistance and proliferation via the ERK/STAT3 signaling pathway in human chronic myelogenous leukemia K562/ADM cells

Zhou

et al. 2018

Oncol Rep

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Acquired resistance to chemotherapy plays a critical role in human drug treatment failure in many tumor types. Multidrug resistance (MDR) to Adriamycin (ADM) also limits the efficacy of therapy in human chronic myelogenous leukemia (CML). The overexpression of drug efflux transporters is one mechanism uderlying MDR. In particular, the consistent activation of MDR1 and MDR‑associated protein 1 (MRP1) is involved in drug resistance. In the present study, ADM‑resistant human CML K562/ADM cells were stably transfected with a Tribbles homolog 2 (TRIB2)‑targeted vector. A CCK‑8 assay showed that the half maximal inhibitory concentration (IC50) of ADM and the cell proliferation were lower in the transfected cells compared with that in the parental K562/ADM cells. The mRNA and protein expression levels of MDR1 and MRP1 were determined by reverse transcription‑polymerase chain reaction (RT‑PCR), RT‑quantitative PCR and western blot analysis. The results showed that the expression of MDR1 and MRP1 was significantly reduced in K562/ADM cells transfected with pGPU6/GFP/Neo‑TRIB2. Due to the downregulation of MDR1 and MRP1, the intracellular accumulation of ADM was increased in the transfected cells compared with that in the parental K562/ADM cells. Therefore, the sensitivity of the K562/ADM cells to ADM was enhanced and proliferation was inhibited. Our research revealed that protein expression of the ERK signaling pathway was inhibited by downregulating TRIB2, indicating that the ERK pathway was involved in cell drug resistance and proliferation. Furthermore, we used the ERK‑specific blocker U0126 to demonstrate this phenomenon. In summary, our research suggested that knockdown of TRIB2 could slow cell growth and reverse resistance, implying that TRIB2 is a potential therapy target for resistant human CML.

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“…6) ABCB1 is a target of the Ras/Raf signaling pathway, suppression of p38, ERK or JNK pathways enhanced sensitivity to chemotherapeutic drugs in multidrug resistant tumor cells. [7][8][9][10] Paris polyphylla var. yunnanensis (Franch.)…”

Section: Introductionmentioning

confidence: 99%

Total Saponins from Paris forrestii Reverse Multidrug Resistance of MCF-7/ADM Cells by Suppression of P-gp via ERK Signaling Pathway

Chai

Yuan

Zhu

et al. 2020

Biological & Pharmaceutical Bulletin

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Our previous study demonstrated that the total saponins from Paris forristii (PCT3)had obvious inhibitory effect on the proliferation of adriamycin-resistant human breast adenocarcinoma cells (MCF-7/ADM), this effect was significantly stronger than that in parental cells (MCF-7). This study was designed to test the reversal effect of PCT3 on MCF-7/ADM cells and to understand its mechanism of action. Results demonstrated that low cytotoxic concentrations of PCT3 (0.3, 1 and 3 µg/ml) reversed resistance of MCF-7/ADM cells to ADM, DDP and 5-FU, with reversal fold of 16.4, 19.5 and 31.7 for ADM, 1.6, 1.4 and 1.4 for DDP, 1.7, 1.8 and 5.6 for 5-FU, respectively. Moreover, PCT3 significantly increased the accumulation of ADM and Rh123 in MCF-7/ADM cells, suggesting that PCT3 may act by affecting the function of drug efflux pump P-gp, which is encoded by MDR1 gene. Both MDR1 gene and P-gp protein expression was downregulated by PCT3 treatment. Further results demonstrated that p38MAPK and ERK pathway was remarkably activated in MCF-7/ADM cells, inhibition of p38 or ERK attenuated P-gp expression. While, only the phosphorylation level of ERK was downregulated by PCT3, indicating that PCT3 sensitized P-gp overexpressed MCF-7/ADM cells to ADM via inhibition of ERK signaling pathway.

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Asclepiasterol, a novel C21 steroidal glycoside derived fromAsclepias curassavica, reverses tumor multidrug resistance by down-regulating P-glycoprotein expression

Cited by 27 publications

References 60 publications

The effects of ultrasound exposure on P-glycoprotein-mediated multidrug resistance in vitro and in vivo

The effects of ultrasound exposure on P-glycoprotein-mediated multidrug resistance in vitro and in vivo

TRIB2 knockdown as a regulator of chemotherapy resistance and proliferation via the ERK/STAT3 signaling pathway in human chronic myelogenous leukemia K562/ADM cells

Total Saponins from <i>Paris forrestii</i> Reverse Multidrug Resistance of MCF-7/ADM Cells by Suppression of P-gp <i>via</i> ERK Signaling Pathway

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