Modulation of P-glycoprotein activity by novel synthetic curcumin derivatives in sensitive and multidrug-resistant T-cell acute lymphoblastic leukemia cell lines
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Edna Ooko
- Tahseen Alsalim
- Bahjat Saeed
- Mohamed EM Saeed
- Onat Kadioglu
- Hanna S Abbo
- Salam JJ Titinchi
- Thomas Efferth
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000380732800024&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1016/j.taap.2016.06.002
- eISSN
- 1096-0333
- Externe Identifier
- Clarivate Analytics Document Solution ID: DS4DY
- PubMed Identifier: 27318188
- ISSN
- 0041-008X
- Zeitschrift
- TOXICOLOGY AND APPLIED PHARMACOLOGY
- Schlüsselwörter
- Multidrug resistance
- P-glycoprotein
- Cancer
- Chemotherapy
- Curcumin derivatives
- Paginierung
- 216 - 233
- Datum der Veröffentlichung
- 2016
- Status
- Published
- Titel
- Modulation of P-glycoprotein activity by novel synthetic curcumin derivatives in sensitive and multidrug-resistant T-cell acute lymphoblastic leukemia cell lines
- Sub types
- Article
- Ausgabe der Zeitschrift
- 305
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- Edna Ooko
- Tahseen Alsalim
- Bahjat Saeed
- Mohamed EM Saeed
- Onat Kadioglu
- Hanna S Abbo
- Salam JJ Titinchi
- Thomas Efferth
- DOI
- 10.1016/j.taap.2016.06.002
- ISSN
- 0041-008X
- Zeitschrift
- Toxicology and Applied Pharmacology
- Sprache
- en
- Paginierung
- 216 - 233
- Datum der Veröffentlichung
- 2016
- Status
- Published
- Herausgeber
- Elsevier BV
- Herausgeber URL
- http://dx.doi.org/10.1016/j.taap.2016.06.002
- Datum der Datenerfassung
- 2022
- Titel
- Modulation of P-glycoprotein activity by novel synthetic curcumin derivatives in sensitive and multidrug-resistant T-cell acute lymphoblastic leukemia cell lines
- Ausgabe der Zeitschrift
- 305
Data source: Crossref
- Abstract
- <h4>Background</h4>Multidrug resistance (MDR) and drug transporter P-glycoprotein (P-gp) represent major obstacles in cancer chemotherapy. We investigated 19 synthetic curcumin derivatives in drug-sensitive acute lymphoblastic CCRF-CEM leukemia cells and their multidrug-resistant P-gp-overexpressing subline, CEM/ADR5000.<h4>Material and methods</h4>Cytotoxicity was tested by resazurin assays. Doxorubicin uptake was assessed by flow cytometry. Binding modes of compounds to P-gp were analyzed by molecular docking. Chemical features responsible for bioactivity were studied by quantitative structure activity relationship (QSAR) analyses. A 7-descriptor QSAR model was correlated with doxorubicin uptake values, IC50 values and binding energies.<h4>Results</h4>The compounds displayed IC50 values between 0.7±0.03 and 20.2±0.25μM. CEM/ADR5000 cells exhibited cross-resistance to 10 compounds, collateral sensitivity to three compounds and regular sensitivity to the remaining six curcumins. Molecular docking studies at the intra-channel transmembrane domain of human P-gp resulted in lowest binding energies ranging from -9.00±0.10 to -6.20±0.02kcal/mol and pKi values from 0.24±0.04 to 29.17±0.88μM. At the ATP-binding site of P-gp, lowest binding energies ranged from -9.78±0.17 to -6.79±0.01kcal/mol and pKi values from 0.07±0.02 to 0.03±0.03μM. CEM/ADR5000 cells accumulated approximately 4-fold less doxorubicin than CCRF-CEM cells. The control P-gp inhibitor, verapamil, partially increased doxorubicin uptake in CEM/ADR5000 cells. Six curcumins increased doxorubicin uptake in resistant cells or even exceeded uptake levels compared to sensitive one. QSAR yielded good activity prediction (R=0.797 and R=0.794 for training and test sets).<h4>Conclusion</h4>Selected derivatives may serve to guide future design of novel P-gp inhibitors and collateral sensitive drugs to combat MDR.
- Addresses
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
- Autoren
- Edna Ooko
- Tahseen Alsalim
- Bahjat Saeed
- Mohamed EM Saeed
- Onat Kadioglu
- Hanna S Abbo
- Salam JJ Titinchi
- Thomas Efferth
- Thomas Efferth
- DOI
- 10.1016/j.taap.2016.06.002
- eISSN
- 1096-0333
- Externe Identifier
- PubMed Identifier: 27318188
- Open access
- false
- ISSN
- 0041-008X
- Zeitschrift
- Toxicology and applied pharmacology
- Schlüsselwörter
- Cell Line, Tumor
- Humans
- Curcumin
- Doxorubicin
- Antineoplastic Agents
- Drug Resistance, Multiple
- Cell Survival
- Quantitative Structure-Activity Relationship
- Drug Resistance, Neoplasm
- Models, Molecular
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2016
- Paginierung
- 216 - 233
- Datum der Veröffentlichung
- 2016
- Status
- Published
- Datum der Datenerfassung
- 2016
- Titel
- Modulation of P-glycoprotein activity by novel synthetic curcumin derivatives in sensitive and multidrug-resistant T-cell acute lymphoblastic leukemia cell lines.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 305
Data source: Europe PubMed Central
- Abstract
- BACKGROUND: Multidrug resistance (MDR) and drug transporter P-glycoprotein (P-gp) represent major obstacles in cancer chemotherapy. We investigated 19 synthetic curcumin derivatives in drug-sensitive acute lymphoblastic CCRF-CEM leukemia cells and their multidrug-resistant P-gp-overexpressing subline, CEM/ADR5000. MATERIAL AND METHODS: Cytotoxicity was tested by resazurin assays. Doxorubicin uptake was assessed by flow cytometry. Binding modes of compounds to P-gp were analyzed by molecular docking. Chemical features responsible for bioactivity were studied by quantitative structure activity relationship (QSAR) analyses. A 7-descriptor QSAR model was correlated with doxorubicin uptake values, IC50 values and binding energies. RESULTS: The compounds displayed IC50 values between 0.7±0.03 and 20.2±0.25μM. CEM/ADR5000 cells exhibited cross-resistance to 10 compounds, collateral sensitivity to three compounds and regular sensitivity to the remaining six curcumins. Molecular docking studies at the intra-channel transmembrane domain of human P-gp resulted in lowest binding energies ranging from -9.00±0.10 to -6.20±0.02kcal/mol and pKi values from 0.24±0.04 to 29.17±0.88μM. At the ATP-binding site of P-gp, lowest binding energies ranged from -9.78±0.17 to -6.79±0.01kcal/mol and pKi values from 0.07±0.02 to 0.03±0.03μM. CEM/ADR5000 cells accumulated approximately 4-fold less doxorubicin than CCRF-CEM cells. The control P-gp inhibitor, verapamil, partially increased doxorubicin uptake in CEM/ADR5000 cells. Six curcumins increased doxorubicin uptake in resistant cells or even exceeded uptake levels compared to sensitive one. QSAR yielded good activity prediction (R=0.797 and R=0.794 for training and test sets). CONCLUSION: Selected derivatives may serve to guide future design of novel P-gp inhibitors and collateral sensitive drugs to combat MDR.
- Date of acceptance
- 2016
- Autoren
- Edna Ooko
- Tahseen Alsalim
- Bahjat Saeed
- Mohamed EM Saeed
- Onat Kadioglu
- Hanna S Abbo
- Salam JJ Titinchi
- Thomas Efferth
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/27318188
- DOI
- 10.1016/j.taap.2016.06.002
- eISSN
- 1096-0333
- Zeitschrift
- Toxicol Appl Pharmacol
- Schlüsselwörter
- Cancer
- Chemotherapy
- Curcumin derivatives
- Multidrug resistance
- P-glycoprotein
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Antineoplastic Agents
- Cell Line, Tumor
- Cell Survival
- Curcumin
- Doxorubicin
- Drug Resistance, Multiple
- Drug Resistance, Neoplasm
- Humans
- Models, Molecular
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
- Quantitative Structure-Activity Relationship
- Sprache
- eng
- Country
- United States
- Paginierung
- 216 - 233
- PII
- S0041-008X(16)30136-3
- Datum der Veröffentlichung
- 2016
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2017
- Titel
- Modulation of P-glycoprotein activity by novel synthetic curcumin derivatives in sensitive and multidrug-resistant T-cell acute lymphoblastic leukemia cell lines.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 305
Data source: PubMed
- Beziehungen:
- Property of