Chaetominine reduces MRP1-mediated drug resistance via inhibiting PI3K/Akt/Nrf2 signaling pathway in K562/Adr human leukemia cells

Yao, Jingyun; Xing, Wei; Lü, Yanhua

doi:10.1016/j.bbrc.2016.03.141

Cited by 43 publications

(36 citation statements)

References 24 publications

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“…Of particular interest, is the ABCC transporter, MRP1, which plays a key role in the chemoresistance of several cancers (24,25) and regulated by PI3K/AKT (26,27). We observed markedly decreased expression of MRP1 protein following MCAM knockdown, suggesting that MRP1 regulation is associated with MCAM expression in chemoresistant cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

MCAM Mediates Chemoresistance in Small-Cell Lung Cancer via the PI3K/AKT/SOX2 Signaling Pathway

et al. 2017

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Despite favorable responses to initial therapy, SCLC relapse occurs within a year exhibiting a multidrug resistant phenotype. Due to limited accessibility of patient tissues for research purpose, SCLC patient derived xenografts (PDXs) have provided the best opportunity to address this limitation. We sought to identify novel mechanisms involved in SCLC chemoresistance. Through in-depth proteomic profiling, we identified MCAM as a markedly upregulated surface receptor in chemoresistant SCLC cell lines that exhibited a mesenchymal phenotype and in chemoresistant PDXs compared to matched treatment-naïve tumors. MCAM is a cell membrane protein whose expression has been implicated in multiple human cancers. MCAM expression is also detected in lung adenocarcinoma; however, its expression and role in SCLC is has not been explored. MCAM knockdown in chemoresistant cells reduced cell proliferation and decreased the IC50 inhibitory concentration of chemotherapeutic drugs. MCAM was found to modulate sensitivity of SCLC cells to chemotherapeutic drugs through up-regulation of MRP1/ABCC1 expression and of the PI3/AKT pathway in a SOX2-dependent manner. Metabolomic profiling revealed that MCAM modulates lactate production in chemoresistant cells that exhibit a distinct metabolic phenotype characterized by low oxidative phosphorylation. MCAM may serve as a novel therapeutic target to overcome chemoresistance in SCLC.

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Section: Resultsmentioning

confidence: 99%

MCAM Mediates Chemoresistance in Small-Cell Lung Cancer via the PI3K/AKT/SOX2 Signaling Pathway

et al. 2017

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“…In essence, a particular tumour can be clinically recognized as MDR through the identification of a unique spectrum of dysregulated expression patterns of multiple mRNA biomarkers [29,30,31,32,33]. However, the discovery of the miRNA and long non-coding RNA (lncRNA) families have created additional layers of genomic regulatory functions [2,34,35,36,37,38,39].…”

Section: Cancer Chemoresistance Manifestations and Development Mecmentioning

confidence: 99%

Influence of microRNAs and Long Non-Coding RNAs in Cancer Chemoresistance

Ayers

Vandesompele

2017

Genes

102

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Innate and acquired chemoresistance exhibited by most tumours exposed to conventional chemotherapeutic agents account for the majority of relapse cases in cancer patients. Such chemoresistance phenotypes are of a multi-factorial nature from multiple key molecular players. The discovery of the RNA interference pathway in 1998 and the widespread gene regulatory influences exerted by microRNAs (miRNAs) and other non-coding RNAs have certainly expanded the level of intricacy present for the development of any single physiological phenotype, including cancer chemoresistance. This review article focuses on the latest research efforts in identifying and validating specific key molecular players from the two main families of non-coding RNAs, namely miRNAs and long non-coding RNAs (lncRNAs), having direct or indirect influences in the development of cancer drug resistance properties and how such knowledge can be utilised for novel theranostics in oncology.

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“…Recently, Nrf2 has been reported to be a pharmacological target to overcome drug resistance. Overexpression of Nrf2 increases chemoresistance; on the contrary, knockdown of Nrf2 sensitizes various cancer cells including liver,6 leukemia,7 neuroblastoma,8 lung,9 breast,10 and pancreatic11 cells to chemotherapeutic drugs. Hence, screening Nrf2 inhibitors as an adjuvant sensitizer to overcome drug resistance is a desirable treatment strategy.…”

Section: Introductionmentioning

confidence: 99%

Ursolic acid sensitizes cisplatin-resistant HepG2/DDP cells to cisplatin via inhibiting Nrf2/ARE pathway

Wu¹,

Zhang

Du³

2016

DDDT

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BackgroundCombinations of adjuvant sensitizers with anticancer drugs is a promising new strategy to reverse chemoresistance. Ursolic acid (UA) is one of the natural pentacyclic triterpene compounds known to have many pharmacological characteristics such as anti-inflammatory and anticancer properties. This study investigates whether UA can sensitize hepatocellular carcinoma cells to cisplatin.Materials and methodsCells were transfected with nuclear factor erythroid-2-related factor 2 (Nrf2) small interfering RNA and Nrf2 complementary DNA by using Lipofectin 2000. The cytotoxicity of cells was investigated by Cell Counting Kit 8 assay. Cell apoptosis, cell cycle, reactive oxygen species, and mitochondrial membrane potential were detected by flow cytometry fluorescence-activated cell sorting. The protein level of Nrf2, NAD(P)H quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST), and heme oxygenase-1 (HO-1) was detected by Western blot analysis.ResultsThe results showed that the reverse index was 2.9- and 9.69-fold by UA of 1.125 μg/mL and 2.25 μg/mL, respectively, for cisplatin to HepG2/DDP cells. UA–cisplatin combination induced cell apoptosis and reactive oxygen species, blocked the cell cycle in G0/G1 phase, and reduced the mitochondrial membrane potential. Mechanistically, UA–cisplatin dramatically decreased the expression of Nrf2 and its downstream genes. The sensibilization of UA–cisplatin combination was diminished in Nrf2 small interfering RNA-transfected HepG2/DDP cells, as well as in Nrf2 complementary DNA-transfected HepG2/DDP cells.ConclusionThe results confirmed the sensibilization of UA on HepG2/DDP cells to cisplatin, which was possibly mediated via the Nrf2/antioxidant response element pathway.

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Chaetominine reduces MRP1-mediated drug resistance via inhibiting PI3K/Akt/Nrf2 signaling pathway in K562/Adr human leukemia cells

Cited by 43 publications

References 24 publications

MCAM Mediates Chemoresistance in Small-Cell Lung Cancer via the PI3K/AKT/SOX2 Signaling Pathway

MCAM Mediates Chemoresistance in Small-Cell Lung Cancer via the PI3K/AKT/SOX2 Signaling Pathway

Influence of microRNAs and Long Non-Coding RNAs in Cancer Chemoresistance

Ursolic acid sensitizes cisplatin-resistant HepG2/DDP cells to cisplatin via inhibiting Nrf2/ARE pathway

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