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Chemosensitizing potential of andrographolide in P-glycoprotein overexpressing multidrug-resistant cancer cell lines
Deepa Swati Lakra1, Pradhapsingh B1, Deepika N1
1Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, Tamil Nadu, India.
Abstract:
The P-glycoprotein (P-gp) plays a major role in the efflux of chemotherapeutic drugs and significantly limits chemotherapy efficacy. Chemosensitizers augment the therapeutic effects of anticancer agents by overcoming drug resistance mechanisms. In this study, the chemosensitizing property of andrographolide (Andro) in P-gp overexpressing multidrug-resistant (MDR) colchicine-selected KBChR 8-5 cells was evaluated. Molecular docking studies showed Andro exhibits higher binding interaction with P-gp than the other two ABC-transporters studied. Further, it inhibits P-gp transport function in a concentration dependant manner in the colchicine-selected KBChR 8-5 cells. Moreover, Andro downregulates P-gp overexpression via NF-κB signaling in these MDR cell lines. MTT-based cell-based assay illustrates that Andro treatment augments the PTX effect in the KBChR 8-5 cells. Further, the Andro plus PTX combination showed enhanced apoptotic cell death in KBChR 8-5 cells compared with PTX alone treatment. Therefore, the results showed that Andro enhances PTX therapeutic effect in the drug-resistant KBChR 8-5 cells.
Insights
Andrographolide (Andro) enhances chemotherapy by inhibiting P-glycoprotein (P-gp) drug efflux. This chemosensitizer boosts paclitaxel
Area of Science:
- Pharmacology
- Molecular Biology
- Cancer Research
Background:
- P-glycoprotein (P-gp) mediates multidrug resistance (MDR) in cancer, limiting chemotherapy efficacy.
- Chemosensitizers are crucial for overcoming MDR and improving anticancer drug effectiveness.
Purpose of the Study:
- To evaluate andrographolide (Andro) as a chemosensitizer in P-gp overexpressing MDR cells.
- To investigate Andro's mechanism in overcoming P-gp-mediated drug resistance.
Main Methods:
- Molecular docking studies to assess Andro's binding affinity to P-gp.
- In vitro assays to evaluate P-gp transport inhibition and Andro's effect on P-gp expression.
- Cell-based assays (MTT) to determine the chemosensitizing effect of Andro in combination with paclitaxel (PTX).
Main Results:
- Andrographolide (Andro) demonstrated strong binding interaction with P-glycoprotein (P-gp).
- Andro inhibited P-gp transport function and downregulated P-gp overexpression via NF-κB signaling.
- Andro significantly augmented the paclitaxel (PTX) effect and enhanced apoptosis in MDR cells.
Conclusions:
- Andrographolide (Andro) effectively overcomes P-glycoprotein (P-gp)-mediated multidrug resistance.
- Andro acts as a potent chemosensitizer, enhancing the therapeutic efficacy of paclitaxel (PTX).
- Andro represents a promising therapeutic agent for overcoming chemotherapy resistance in cancer treatment.
