Suppression of BCRP Expression and Restoration of Sensitivity to Chemotherapy in Multidrug-Resistant Hepatocellular Carcinoma Cell Line HEPG2/ADM by RNA Interference

Li, Hongyang; Zhou, Shi‐Ping; Li, Tao; Liu, Zuojin; Wu, Jinfeng; Zeng, Gui-Li; Liu, Changan; Gong, Jianping

doi:10.5754/hge11781

Cited by 9 publications

(11 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this case both decrease of ABC 0 and increase of CYP levels results in lower EC 50 values, while increase of ABC 0 and decrease of CYP level results in higher EC 50 values. These results are in agreement with RNA silencing experiments, where cytotoxicity to doxorubicin increased after silencing of ABCG2 [ 22 ], whereas cytotoxicity to cyclophosphamide decreased after the silencing of CYP3A4 [ 21 ].…”

Section: Resultssupporting

confidence: 88%

“…This opened the possibility for the calculation of in silico cytotoxicity curves resembling experimentally obtained results. Our results of in silico toxicity analysis are in agreement with RNA silencing experiments described in the literature [ 21 , 22 ].…”

Section: Introductionsupporting

confidence: 91%

“…6 ). The toxicity module—despite being simplified—is able to qualitatively reproduce the results of cell killing experiments [ 21 , 22 ]. An important limitation of our model in this regard is that in order to provide predictive systemic effects, the toxicological properties of the modeled drug metabolites have to be independently estimated.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

A Novel Mathematical Model Describing Adaptive Cellular Drug Metabolism and Toxicity in the Chemoimmune System

et al. 2015

View full text Add to dashboard Cite

Cells cope with the threat of xenobiotic stress by activating a complex molecular network that recognizes and eliminates chemically diverse toxic compounds. This “chemoimmune system” consists of cellular Phase I and Phase II metabolic enzymes, Phase 0 and Phase III ATP Binding Cassette (ABC) membrane transporters, and nuclear receptors regulating these components. In order to provide a systems biology characterization of the chemoimmune network, we designed a reaction kinetic model based on differential equations describing Phase 0–III participants and regulatory elements, and characterized cellular fitness to evaluate toxicity. In spite of the simplifications, the model recapitulates changes associated with acquired drug resistance and allows toxicity predictions under variable protein expression and xenobiotic exposure conditions. Our simulations suggest that multidrug ABC transporters at Phase 0 significantly facilitate the defense function of successive network members by lowering intracellular drug concentrations. The model was extended with a novel toxicity framework which opened the possibility of performing in silico cytotoxicity assays. The alterations of the in silico cytotoxicity curves show good agreement with in vitro cell killing experiments. The behavior of the simplified kinetic model suggests that it can serve as a basis for more complex models to efficiently predict xenobiotic and drug metabolism for human medical applications.

show abstract

Section: Resultssupporting

confidence: 88%

Section: Introductionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A Novel Mathematical Model Describing Adaptive Cellular Drug Metabolism and Toxicity in the Chemoimmune System

et al. 2015

View full text Add to dashboard Cite

show abstract

“…BCRP transports a wide range of conjugated and unconjugated xenobiotics and was demonstrated to mediate resistance to chemotherapeutic agents like daunorubicin and mitoxantrone [ 15 , 16 ]. As far as HCC is concerned, there is evidence associating BCRP overexpression with resistance to doxorubicin in vitro [ 17 ]. It was reported that Sfb intracellular accumulation is modulated by P-gp, MRP2 and BCRP [ 18 , 19 ] due to the extrusion of either Sfb itself or its metabolites, which exhibit also chemical properties typical of P-gp and MRP2 substrates [ 10 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Regulation of Multidrug Resistance Proteins by Genistein in a Hepatocarcinoma Cell Line: Impact on Sorafenib Cytotoxicity

et al. 2015

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide. Sorafenib is the only drug available that improves the overall survival of HCC patients. P-glycoprotein (P-gp), Multidrug resistance-associated proteins 2 and 3 (MRP2 and 3) and Breast cancer resistance protein (BCRP) are efflux pumps that play a key role in cancer chemoresistance. Their modulation by dietary compounds may affect the intracellular accumulation and therapeutic efficacy of drugs that are substrates of these transporters. Genistein (GNT) is a phytoestrogen abundant in soybean that exerts its genomic effects through Estrogen-Receptors and Pregnane-X-Receptor (PXR), which are involved in the regulation of the above-mentioned transporters. We evaluated the effect of GNT on the expression and activity of P-gp, MRP2, MRP3 and BCRP in HCC-derived HepG2 cells. GNT (at 1.0 and 10 μM) increased P-gp and MRP2 protein expression and activity, correlating well with an increased resistance to sorafenib cytotoxicity as detected by the methylthiazole tetrazolium (MTT) assay. GNT induced P-gp and MRP2 mRNA expression at 10 but not at 1.0 μM concentration suggesting a different pattern of regulation depending on the concentration. Induction of both transporters by 1.0 μM GNT was prevented by cycloheximide, suggesting translational regulation. Downregulation of expression of the miR-379 by GNT could be associated with translational regulation of MRP2. Silencing of PXR abolished P-gp induction by GNT (at 1.0 and 10 μM) and MRP2 induction by GNT (only at 10 μM), suggesting partial mediation of GNT effects by PXR. Taken together, the data suggest the possibility of nutrient-drug interactions leading to enhanced chemoresistance in HCC when GNT is ingested with soy rich diets or dietary supplements.

show abstract

“…Specific siRNAs targeting chemoresistant genes designed using RNAi technology have shown considerable potential in reversing MDR (Maddalena et al, 2011;Li et al, 2012;Zhao et al, 2012;Yin et al, 2012). In the current study, we constructed recombinant lentivirus containing siRNA targeting GST-π and polβ genes.…”

Section: Discussionmentioning

confidence: 99%

Roles of GST-π and polβ Genes in Chemoresistance of Esophageal Carcinoma Cells

Tang

Xing²,

Li³

et al. 2013

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

Suppression of BCRP Expression and Restoration of Sensitivity to Chemotherapy in Multidrug-Resistant Hepatocellular Carcinoma Cell Line HEPG2/ADM by RNA Interference

Cited by 9 publications

References 0 publications

A Novel Mathematical Model Describing Adaptive Cellular Drug Metabolism and Toxicity in the Chemoimmune System

A Novel Mathematical Model Describing Adaptive Cellular Drug Metabolism and Toxicity in the Chemoimmune System

Regulation of Multidrug Resistance Proteins by Genistein in a Hepatocarcinoma Cell Line: Impact on Sorafenib Cytotoxicity

Roles of GST-π and polβ Genes in Chemoresistance of Esophageal Carcinoma Cells

Contact Info

Product

Resources

About