Pinostrobin and Tectochrysin Conquer Multidrug-Resistant Cancer Cells via Inhibiting P-Glycoprotein ATPase

Enhanced drug efflux through ATP-binding cassette transporters, particularly P-glycoprotein (P-gp), is a key mechanism underlying multidrug resistance (MDR). In the present study, we investigated the inhibitory effects of pinostrobin and tectochrysin on P-gp in MDR cancer cells and the underlying me...

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Published in:Pharmaceuticals (Basel, Switzerland) Switzerland), 2023-01, Vol.16 (2), p.205
Main Authors: Wu, I-Ting, Kuo, Chan-Yen, Su, Ching-Hui, Lan, Yu-Hsuan, Hung, Chin-Chuan
Format: Article
Language:English
Subjects:
ABC transporters
Adenosine triphosphatase
Alzheimer's disease
Antimitotic agents
Antineoplastic agents
Apoptosis
ATPase
Bioflavonoids
Breast cancer
Cancer
Cancer therapies
Care and treatment
Cell cycle
Cell division
Chemical properties
Chemotherapy
Dosage and administration
drug efflux
Drug resistance
Drugs
Enzyme kinetics
Flavones
Flavonoid
Flavonoids
Glycoproteins
Health aspects
Metabolites
multidrug resistance
pinostrobin
tectochrysin
Testing
Tumor necrosis factor-TNF
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Summary:Enhanced drug efflux through ATP-binding cassette transporters, particularly P-glycoprotein (P-gp), is a key mechanism underlying multidrug resistance (MDR). In the present study, we investigated the inhibitory effects of pinostrobin and tectochrysin on P-gp in MDR cancer cells and the underlying mechanisms. Fluorescence substrate efflux assays, multidrug resistance 1 (MDR1) shift assays, P-gp ATPase activity assays, Western blotting, and docking simulation were performed. The potential of the test compounds for MDR reversal and the associated molecular mechanisms were investigated through cell viability assay, cell cycle analysis, apoptosis assay, and further determining the combination index. Results demonstrated that pinostrobin and tectochrysin were not the substrates of P-gp, nor did they affect the expression of this transporter. Both compounds noncompetitively inhibited the efflux of rhodamine 123 and doxorubicin through P-gp. Furthermore, they resensitized MDR cancer cells to chemotherapeutic drugs, such as vincristine, paclitaxel, and docetaxel; thus, they exhibited strong MDR reversal effects. Our findings indicate that pinostrobin and tectochrysin are effective P-gp inhibitors and promising candidates for resensitizing MDR cancer cells.
ISSN:1424-8247
1424-8247
DOI:10.3390/ph16020205