A Quantitative Structure-Activity Relationship for the Modulation Effects of Flavonoids on P-Glycoprotein-Mediated Transport

Abstract

Regular ArticleCancer chemotherapy has been of limited success because of intrinsic or acquired resistance of cancer cells to a broad range of chemically and functionally distinct anticancer agents, a phenomenon termed multidrug resistance (MDR). Tumor cells develop drug resistance through various mechanisms, such as overexpression of drug efflux transporters like P-glycoprotein (P-gp), changes in topoisomerase activity, modifications to glutathione S-transferase, and altered expressions of apoptosis-associated protein, Bcl-2, and tumor suppressor protein, p53. Of these, overexpression of P-gp is the critical factor. P-gp (ABCB1), a 170-kDa plasma glycoprotein encoded by the human MDR1 gene and murine mdr1a, mdr1b, and mdr2 genes, belongs to the ATP-binding cassette family of transporters.1) It is an integral membrane protein with two homologous halves, each consisting of one hydrophobic loop with six transmembrane domains (TMDs) and one hydrophilic nucleotide-binding domain (NBD). Binding and transport of substrates is mediated by TMD using energy derived from the hydrolysis of ATP at the NBD. 2,3) Numerous studies suggest that the principal physiological role of P-gp is to protect the organism from toxic substances. This efflux pump is also present in many normal tissues including the epithelium of the gastrointestinal tract, renal proximal tubules, canalicular surface of hepatocytes, and the endothelial cell surfaces comprising the blood-brain barrier. P-gp in the intestines, liver, and kidneys may play important roles in the absorption, distribution, or excretion of drugs. 4)P-gp acts as an energy-dependent efflux pump with a broad specificity for chemically unrelated hydrophobic compounds, such as paclitaxel, anthracyclines, Vinca alkaloids, dexamethasone, lidocaine, erythromycin, and protease inhibitors. Therefore, its overexpression is a major cause of failure in human cancer chemotherapy.MDR cells can be sensitized to anticancer drugs when treated with a P-gp inhibitor, otherwise known as a chemosensitizer. Compounds such as verapamil, dihydropyridine analogs, quinidine, and cyclosporin A are capable of suppressing P-gp function due to their inhibitory properties.Meanwhile, these compounds have an intrinsic toxicity because they are pharmacologically active. They cannot be used safely at dosages required for MDR reversal. The search for chemosensitizers, which have the advantage of being a non-transportable inhibitor without side effects, has led to a great deal of research in plant-derived flavonoids.Flavonoids are constituents of fruits, vegetables, and plantderived beverages, such as coffee, tea, and red wine as well as components of herbal-containing dietary supplements (e.g., Silybum marianum, Alpina officinarum, and Hypericum perforatum). More than 4000 naturally occurring flavonoids have been discovered, 5) arising from the various combinations of multiple hydroxyl and methoxyl group substituents of the basic flavonoid skeleton. The classes of flavonoids include chalcones, flavones, flavonols, fla...

Twist Confers Chemoresistance to Anthracyclines in Bladder Cancer through Upregulating P-Glycoprotein

“…Verapamil inhibits P-gp through competition for binding sites [26,38]. In our study, nontoxic doses of verapamil were able to sensitize 253J cells to DOX and THP, suggesting that P-gp is critical to chemoresistance in 253 cells.…”

Flavonoid interactions during digestion, absorption, distribution and metabolism: a sequential structure–activity/property relationship-based approach in the study of bioavailability and bioactivity

“…Although predictive, direct interpretation of which molecular descriptors were responsible for P-glycoprotein inhibition is rather not obvious due to PCA being a diminution technique. Another approach was made by Sheu et al (2010), wherein SMLR was used to create a QSAR model from an in vitro analysis of 22 flavonoids using human colorectal carcinoma (HCT15) cells. The model with the highest adjusted R 2 was reported as (Sheu et al, 2010) Adjusted R 2 ¼ 0:7126, F ¼ 4:53, p 5 0:02 À Á…”

Dietary Flavonoids Modulate CYP2C to Improve Drug Oral Bioavailability and Their Qualitative/Quantitative Structure–Activity Relationship

“…The QSAR model was constructed using the method described by Sheu et al (26) with a slight modification, and was based on a stepwise linear regression analysis with entry criteria set as F < 0.05 and removal criteria set as F > 0.1. SPSS statistical software (version 17.0; IBM Inc., Chicago, IL) was used to determine statistically significant relationships between the dependent variable (enzymatic inhibition) and the independent variables (flavonoid structural units or compound skeleton).…”