Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators

Abstract

Multidrug resistance (MDR) in cancer is one of the main limitations for chemotherapy success. Numerous mechanisms are behind the MDR phenomenon wherein the overexpression of the ATP-binding cassette (ABC) transporter proteins P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance protein 1 (MRP1) is highlighted as a prime factor. Natural product-derived compounds are being addressed as promising ABC transporter modulators to tackle MDR. Flavonoids and terpenoids have been extensively explored in this field as mono or dual modulators of these efflux pumps. Nitrogen-bearing moieties on these scaffolds were proved to influence the modulation of ABC transporters efflux function. This review highlights the potential of semisynthetic nitrogen-containing flavonoid and terpenoid derivatives as candidates for the design of effective MDR reversers. A brief introduction concerning the major role of efflux pumps in multidrug resistance, the potential of natural product-derived compounds in MDR reversal, namely natural flavonoid and terpenoids, and the effect of the introduction of nitrogen-containing groups are provided. The main modifications that have been performed during last few years to generate flavonoid and terpenoid derivatives, bearing nitrogen moieties, such as aliphatic, aromatic and heterocycle amine, amide, and related functional groups, as well as their P-gp, MRP1 and BCRP inhibitory activities are reviewed and discussed.

Elevated ABCB1 Expression Confers Acquired Resistance to Aurora Kinase Inhibitor GSK-1070916 in Cancer Cells

“…ABCB1 (also known as MDR1 or P-glycoprotein) was the first ABC transporter to be identified by Ling et al and is by far the most studied MDR-related efflux pump ( Juliano and Ling, 1976 ). ABCB1 is constitutively expressed in organs and physiological barriers, including kidney, intestine, and the blood-brain barrier ( Gonçalves et al, 2020 ). It has been extensively reported that overexpression of ABCB1 in cancer cells can confer resistance to chemotherapeutic agents such as paclitaxel, vincristine, colchicine, as well as tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib ( Dohse et al, 2006 ; Hegedus et al, 2009 ).…”

Computer‐Aided Search for 5‐Arylideneimidazolone Anticancer Agents Able To Overcome ABCB1‐Based Multidrug Resistance

“…Despite higher safety of the new compounds, various disadvantages associated with them have been reported. Currently, there are studies focused on synthetic modifications of natural products in order to boost pharmacokinetic parameters [10][11][12][13]. At the continuous absence of ABCB1-targeted "adjuvants" in pharmaceutical market, and taking into account their potential advantages for the cancer therapy development, the search for ABCB1 modulators is still a great challenge of pharmaceutical 10.1002/cmdc.202100252…”

Potential Herb–Drug Interactions in the Management of Age-Related Cognitive Dysfunction

“…have already been reported as inhibitors of several CYP enzymes (e.g., the noncompetitive inhibition of CYP2C9 caused by genistein and daidzein [ 245 ]). Both flavonoids and terpenoids have the ability to modulate ABC transporters [ 192 , 617 ], which can be advantageous for drugs with poor absorption, but can also lead to toxic plasma drug concentrations, especially for narrow therapeutic window drugs.…”

“…have already been reported as inhibitors of several CYP enzymes (e.g., the n petitive inhibition of CYP2C9 caused by genistein and daidzein [245]). Both fla and terpenoids have the ability to modulate ABC transporters [192,617], which ca vantageous for drugs with poor absorption, but can also lead to toxic plasma dr centrations, especially for narrow therapeutic window drugs. 4, apigenin, EGCG, g hypericin, quercetin, caffeic acid, catechin, cinnamaldehyde, curcumin, delphinid olin, naringenin, puerarin, rosmarinic acid, and resveratrol show the capacity to with all nine drugs.…”