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Modulation of P-glycoprotein activity by novel synthetic curcumin derivatives in sensitive and multidrug-resistant
Edna Ooko1, Tahseen Alsalim2, Bahjat Saeed2
1Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
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.
Insights
Synthetic curcumin derivatives show promise in overcoming multidrug resistance (MDR) in cancer chemotherapy. Some derivatives enhanced doxorubicin uptake in resistant cells, suggesting potential for new P-glycoprotein (P-gp) inhibitors.
Area of Science:
- Medicinal Chemistry
- Cancer Pharmacology
- Molecular Biology
Background:
- Multidrug resistance (MDR) and P-glycoprotein (P-gp) are significant challenges in cancer chemotherapy.
- This study investigates synthetic curcumin derivatives for their efficacy against drug-sensitive and P-gp-overexpressing resistant leukemia cells.
Purpose of the Study:
- To evaluate the cytotoxicity of 19 synthetic curcumin derivatives in leukemia cell lines.
- To assess the impact of these derivatives on doxorubicin uptake in multidrug-resistant cells.
- To elucidate the binding interactions with P-gp and identify structure-activity relationships.
Main Methods:
- Cytotoxicity assessed via resazurin assays.
- Doxorubicin uptake quantified using flow cytometry.
- Molecular docking and quantitative structure-activity relationship (QSAR) analyses were employed to understand compound-P-gp interactions and predict bioactivity.
Main Results:
- Curcumin derivatives exhibited varying IC50 values, with some showing cross-resistance and others collateral sensitivity in resistant cells.
- Molecular docking revealed favorable binding energies at both the transmembrane domain and ATP-binding site of P-gp.
- Six curcumin derivatives significantly increased doxorubicin uptake in resistant cells, with some exceeding levels in sensitive cells; QSAR models provided good predictive accuracy.
Conclusions:
- Certain synthetic curcumin derivatives demonstrate potential as modulators of P-gp activity.
- These compounds could serve as a basis for developing novel P-gp inhibitors or collateral-sensitive drugs to overcome MDR in cancer therapy.
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