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.
Highlights
Despite the fact recent advances in cancer treatment, such as targeted therapy and immunotherapy, have contributed significantly to improving the disease-free survival rate and quality of life of cancer patients, cancer is still the second cause of death and morbidity in Europe, with more than 1.9 million deaths each year [1]
Over the past few decades, the mechanism most frequently associated with the development of multidrug resistance (MDR) in cancer is the over-expression of ATP-binding cassette (ABC) transporter proteins either at the plasma membrane or in intracellular vesicles
Results revealed that derivatives bearing a four units polyethylene glycol (PEG) linker, such as compound (EC50 = 0.95 μM) and its dehydroxylated derivative (EC50 = 0.22 μM), displayed significantly higher potency to modulate P-gp-mediated paclitaxel resistance than the Copper(I) catalyzed Huisgen 1,3-dipolar cycloaddition conditions were used to prepare a vast panel of triazole bridged flavonoid homo- and heterodimer derivatives that induced relevant multidrug resistance protein 1 (MRP1) inhibition (EC50 ranging from 0.053 to 0.298 μM) and presented reduced toxicity, having high selective indexes ranging from 190 to 1887
Summary
Despite the fact recent advances in cancer treatment, such as targeted therapy and immunotherapy, have contributed significantly to improving the disease-free survival rate and quality of life of cancer patients, cancer is still the second cause of death and morbidity in Europe, with more than 1.9 million deaths each year [1]. The development of multidrug resistance (MDR), a phenomenon that occurs when tumors become tolerant to multiple and structurally unrelated anticancer drugs, represents one of the major obstacles to the long-term success of chemotherapy regimens. This phenomenon, that can be intrinsic, when exists before treatment, or acquired, when develops after therapy, is responsible for most cases of cancer relapses and recurrence associated with high rates of cancer-related deaths [2]. Molecules 2020, 25, 3364 the tumor microenvironment, surviving of cancer stem cells that escape from conventional therapies, among others [3,4,5,6]
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