Modulation of P-glycoprotein activity by novel synthetic curcumin derivatives in sensitive and multidrug-resistant T-cell acute lymphoblastic leukemia cell lines.
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.



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.



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).



Selected derivatives may serve to guide future design of novel P-gp inhibitors and collateral sensitive drugs to combat MDR.
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Edna
E
Ooko
Department of Chemistry, College of Education for Pure Sciences, University of Basrah, P.O. Box 49 Basrah, Al Basrah, Iraq.
Tahseen
T
Alsalim
Department of Chemistry, College of Education for Pure Sciences, University of Basrah, P.O. Box 49 Basrah, Al Basrah, Iraq.
Bahjat
B
Saeed
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Mohamed E M
MEM
Saeed
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Onat
O
Kadioglu
Department of Chemistry, University of the Western Cape, P/B X17, Bellville, 7535 Cape Town, South Africa.
Hanna S
HS
Abbo
Department of Chemistry, University of the Western Cape, P/B X17, Bellville, 7535 Cape Town, South Africa. Electronic address: stitinchi@uwc.ac.za.
Salam J J
SJJ
Titinchi
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany. Electronic address: efferth@uni-mainz.de.
Thomas
T
Efferth
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008958:Models, Molecular; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; D021281:Quantitative Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004317:Doxorubicin; D003474:Curcumin
Cancer; Chemotherapy; Curcumin derivatives; Multidrug resistance; P-glycoprotein