Genomic and transcriptomic profiling of resistant CEM/ADR-5000 and sensitive CCRF-CEM leukaemia cells for unravelling the full complexity of multi-factorial multidrug resistance

Kadioglu, Onat; Cao, Jingming; Kosyakova, Nadezda; Mrasek, Kristin; Liehr, Thomas; Efferth, Thomas

doi:10.1038/srep36754

Cited by 41 publications

(36 citation statements)

References 107 publications

(109 reference statements)

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“…Therefore, it was a pleasing result that the expression of P-gp/ MDR1 in the NCI cell line panel did not correlate with cellular response to oridonin, which implies that P-gp does not confer resistance to oridonin. In addition, multidrug-resistant CEM/ADR5000 cells with overexpression of various ABC transporters including P-gp/ MDR1 (400-fold) ( Kadioglu et al, 2016a ) revealing high degrees of resistance to well-known anticancer drugs such as doxorubicin (1036-fold), vincristine (613-fold), docetaxel (435-fold), and many others ( Efferth et al, 2008 ) were even slightly more sensitive to oridonin than the parental, wild-type, drug-sensitive CCRF-CEM tumor cells. It can be speculated that oridonin successfully kills otherwise unresponsive, multidrug-resistant tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of P-gp is causatively linked to accelerated efflux of chemotherapeutic agents ( Kadioglu et al, 2016b ) such as doxorubicin, daunorubicin, vincristine, etoposide, colchicine, camptothecins, and methotrexate ( Dean, 2009 ). For instance, P-gp-overexpressing leukemia cells involve doxorubicin resistance compared to the sensitive subline ( Kadioglu et al, 2016a ). BCRP is involved in the efflux of mitoxantrone, topotecan, doxorubicin, daunorubicin, irinotecan, imatinib, and methotrexate ( Dean, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

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Oridonin Targets Multiple Drug-Resistant Tumor Cells as Determined by in Silico and in Vitro Analyses

et al. 2018

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Drug resistance is one of the main reasons of chemotherapy failure. Therefore, overcoming drug resistance is an invaluable approach to identify novel anticancer drugs that have the potential to bypass or overcome resistance to established drugs and to substantially increase life span of cancer patients for effective chemotherapy. Oridonin is a cytotoxic diterpenoid isolated from Rabdosia rubescens with in vivo anticancer activity. In the present study, we evaluated the cytotoxicity of oridonin toward a panel of drug-resistant cancer cells overexpressing ABCB1, ABCG2, or ΔEGFR or with a knockout deletion of TP53. Interestingly, oridonin revealed lower degree of resistance than the control drug, doxorubicin. Molecular docking analyses pointed out that oridonin can interact with Akt/EGFR pathway proteins with comparable binding energies and similar docking poses as the known inhibitors. Molecular dynamics results validated the stable conformation of oridonin docking pose on Akt kinase domain. Western blot experiments clearly revealed dose-dependent downregulation of Akt and STAT3. Pharmacogenomics analyses pointed to a mRNA signature that predicted sensitivity and resistance to oridonin. In conclusion, oridonin bypasses major drug resistance mechanisms and targets Akt pathway and might be effective toward drug refractory tumors. The identification of oridonin-specific gene expressions may be useful for the development of personalized treatment approaches.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Oridonin Targets Multiple Drug-Resistant Tumor Cells as Determined by in Silico and in Vitro Analyses

et al. 2018

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“…First, we analyzed the antiproliferative properties of the panel compounds in vitro against two representative leukemia cell lines, i.e., the drug-sensitive CCRF-CEM and its multidrug-resistant counterpart CEM/ADR5000. The two leukemia cell lines were selected for their studied genotypes and gene expression profiles [ 20 ]. Results are shown in Table 1 .…”

Section: Resultsmentioning

confidence: 99%

Antiproliferative Properties of a Few Auranofin-Related Gold(I) and Silver(I) Complexes in Leukemia Cells and their Interferences with the Ubiquitin Proteasome System

et al. 2020

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A group of triethylphosphine gold(I) and silver(I) complexes, structurally related to auranofin, were prepared and investigated as potential anticancer drug candidates. The antiproliferative properties of these metal compounds were assessed against two leukemia cell lines, i.e., CCRF-CEM and its multidrug-resistant counterpart, CEM/ADR5000. Interestingly, potent cytotoxic effects were disclosed for both series of compounds against leukemia cells, with IC50 values generally falling in the low-micromolar range, the gold derivatives being on the whole more effective than the silver analogues. Some initial structure-function relationships were drawn. Subsequently, the ability of the study compounds to inhibit the three main catalytic activities of the proteasome was investigated. Different patterns of enzyme inhibition emerged for the various metal complexes. Notably, gold compounds were able to inhibit effectively both the trypsin-like and chymotrypsin-like proteasome activities, being less effective toward the caspase-like catalytic activity. In most cases, a significant selectivity of the study compounds toward the proteasome proteolytic activities was detected when compared to other proteases. The implications of the obtained results are discussed.

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“…CEM/ADR5000 cells were treated with 5000 ng/mL doxorubicin (Medical Center, Johannes Gutenberg University, Mainz, Germany) once per week to retain their resistance phenotype. The MDR profile has been previously reported [ 63 , 64 , 65 ]. Cells were passaged twice a week and then used for experiments in the logarithmic phase.…”

Section: Methodsmentioning

confidence: 98%

Treatment of Multidrug-Resistant Leukemia Cells by Novel Artemisinin-, Egonol-, and Thymoquinone-Derived Hybrid Compounds

et al. 2018

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Two major obstacles for successful cancer treatment are the toxicity of cytostatics and the development of drug resistance in cancer cells during chemotherapy. Acquired or intrinsic drug resistance is responsible for almost 90% of treatment failure. For this reason, there is an urgent need for new anticancer drugs with improved efficacy against cancer cells, and with less toxicity on normal cells. There are impressive examples demonstrating the success of natural plant compounds to fight cancer, such as Vinca alkaloids, taxanes, and anthracyclines. Artesunic acid (ARTA), a drug for malaria treatment, also exerts cytotoxic activity towards cancer cells. Multidrug resistance often results from drug efflux pumps (ABC-transporters) that reduce intracellular drug levels. Hence, it would be interesting to know, whether ARTA could overcome drug resistance of tumor cells, and in what way ABC-transporters are involved. Different derivatives showing improved features concerning cytotoxicity and pharmacokinetic behavior have been developed. Considering both drug sensitivity and resistance, we chose a sensitive and a doxorubicin-resistant leukemia cell line and determined the killing effect of ARTA on these cells. Molecular docking and doxorubicin efflux assays were performed to investigate the interaction of the derivatives with P-glycoprotein. Using single-cell gel electrophoresis (alkaline comet assay), we showed that the derivatives of ARTA induce DNA breakage and accordingly programmed cell death, which represents a promising strategy in cancer treatment. ARTA activated apoptosis in cancer cells by the iron-mediated generation of reactive oxygen species (ROS). In conclusion, ARTA derivatives may bear the potential to be further developed as anticancer drugs.

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Genomic and transcriptomic profiling of resistant CEM/ADR-5000 and sensitive CCRF-CEM leukaemia cells for unravelling the full complexity of multi-factorial multidrug resistance

Cited by 41 publications

References 107 publications

Oridonin Targets Multiple Drug-Resistant Tumor Cells as Determined by in Silico and in Vitro Analyses

Oridonin Targets Multiple Drug-Resistant Tumor Cells as Determined by in Silico and in Vitro Analyses

Antiproliferative Properties of a Few Auranofin-Related Gold(I) and Silver(I) Complexes in Leukemia Cells and their Interferences with the Ubiquitin Proteasome System

Treatment of Multidrug-Resistant Leukemia Cells by Novel Artemisinin-, Egonol-, and Thymoquinone-Derived Hybrid Compounds

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