Ellagic Acid and Schisandrins: Natural Biaryl Polyphenols with Therapeutic Potential to Overcome Multidrug Resistance in Cancer

cells Review Ellagic Acid and Schisandrins: Natural Biaryl Polyphenols with Therapeutic Potential to Overcome Multidrug Resistance in Cancer Sabesan Yoganathan 1,* , Anushan Alagaratnam 1,2, Nikita Acharekar 1 and Jing Kong 1 1 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, Queens, NY 11439, USA; [email protected] (A.A.); [email protected] (N.A.); [email protected] (J.K.) 2 Department of Chemistry, St. John’s College of Liberal Arts and Sciences, St. John’s University, 8000 Utopia Parkway, Queens, NY 11439, USA * Correspondence: [email protected] Abstract: Multidrug resistance (MDR) is one of the major clinical challenges in cancer treatment and compromises the effectiveness of conventional anticancer chemotherapeutics. Among known mechanisms of drug resistance, drug efflux via ATP binding cassette (ABC) transporters, namely P-glycoprotein (P-gp) has been characterized as a major mechanism of MDR. The primary function of ABC transporters is to regulate the transport of endogenous and exogenous small molecules across the membrane barrier in various tissues. P-gp and similar efflux pumps are associated with MDR because of their overexpression in many cancer types. One of the intensively studied approaches to overcome this mode of MDR involves development of small molecules to modulate P-gp activity. Citation: Yoganathan, S.; This strategy improves the sensitivity of cancer cells to anticancer drugs that are otherwise ineffective. Alagaratnam, A.; Acharekar, N.; Although multiple generations of P-gp inhibitors have been identified to date, reported compounds Kong, J. Ellagic Acid and have demonstrated low clinical efficacy and adverse effects. More recently, natural polyphenols have Schisandrins: Natural Biaryl emerged as a promising class of compounds to address P-gp linked MDR. This review highlights Polyphenols with Therapeutic the chemical structure and anticancer activities of selected members of a structurally unique class of Potential to Overcome Multidrug ‘biaryl’ polyphenols. The discussion focuses on the anticancer properties of ellagic acid, ellagic acid Resistance in Cancer. Cells 2021, 10, 458. https://doi.org/10.3390/ derivatives, and schisandrins. Research reports regarding their inherent anticancer activities and cells10020458 their ability to sensitize MDR cell lines towards conventional anticancer drugs are highlighted here. Additionally, a brief discussion about the axial chirality (i.e., atropisomerism) that may be introduced Academic Editors: Martin Michaelis, into these natural products for medicinal chemistry studies is also provided. Jindˇrich Cinˇ átl and Mark N. Wass Keywords: anticancer drugs; cancer; multidrug resistance; polyphenols; ellagic acid; schisandrin; Received: 25 January 2021 quercetin; atropisomers; biaryl natural products Accepted: 19 February 2021 Published: 21 February 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in Cancer continues to be a major public health burden and places significant stress on published maps and institutional affil- global economy. Despite being a non-communicable disease, it is the second leading cause iations. of death in the United States and in Europe [1]. On a global scale, one in six deaths is linked to cancer, and about 70% of deaths occur in low- and middle-income countries [1]. In 2018, approximately 9.6 million people died from various types of cancer [2]. Among the many different therapeutic interventions available, chemotherapeutics continue to be one of the Copyright: © 2021 by the authors. primary choices for treating various types of metastatic cancer [3,4]. Vinblastine, paclitaxel, Licensee MDPI, Basel, Switzerland. doxorubicin (Dox), docetaxel, etoposide, cisplatin, 5-fluorouracil (5-FU), cyclophosphamide, This article is an open access article and imatinib are some of the widely used drugs for the treatment of cancer (Figure1)[ 3,5]. distributed under the terms and These agents are natural products, natural product derivatives, or synthetic molecules, conditions of the Creative Commons and have been developed to target different cellular pathways. Although many anticancer Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ agents are readily available, drug resistance renders these conventional chemotherapeutics 4.0/). ineffective during cancer therapy. Cells 2021, 10, 458. https://doi.org/10.3390/cells10020458 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 16 Cells 2021, 10, 458 2 of 14 Although many anticancer agents are readily available, drug resistance renders these conventional chemotherapeutics ineffective during cancer therapy. FigureFigure 1. Structures 1. Structures of of selected selected examplesexamples of of clinically clinically used used anticancer anticancer drugs. drugs. DuringDuring the the course course ofof aa treatmenttreatment regimen, cancer cancer cells cells transform transform and and develop develop re- resis- sistance to these chemotherapeutics [6,7]. If a specific type of cancer exhibits drug re- tance to these chemotherapeutics [6,7]. If a specific type of cancer exhibits drug resistance sistance to a broader selection of drugs, the phenomenon is generally referred to as devel- to a broader selection of drugs, the phenomenon is generally referred to as development of opment of multidrug resistance (MDR) [7,8]. Some of the ways cancer cells develop drug multidrugresistance resistance include (a) (MDR)heightened [7,8 DNA]. Some repair, of the (b) waysreduced cancer drug uptake, cells develop (c) enhanced drug drug resistance includeefflux, (a) (d) heightenedmutation of drug DNA targets, repair, (e) (b) chan reducedges in the drug inherent uptake, apop (c)totic enhanced process, and drug (f) efflux, (d)increased mutation drug of drug metabolism targets, [8]. (e) changesAs an example, in the inherentMDR to paclitaxel apoptotic has process, been attributed and (f) increased to drugincreased metabolism levels of [8 ].proteins As an such example, as mitoge MDRn-activated to paclitaxel protein has kina beenses attributed(MAPKs), protein to increased levelskinase of proteinsB (PKB or such Akt), as and mitogen-activated nuclear factor-κB (NF- proteinκB), kinasesand overexpression (MAPKs), of protein a type kinaseof B (PKBATP-binding or Akt), and cassette nuclear (ABC) factor- transporter,κB (NF- referredκB), and to overexpression as P-glycoprotein of (P-gp) a type [9,10]. of ATP-binding Drug cassetteefflux (ABC)mediated transporter, by ABC transporters referred tohas as been P-glycoprotein identified as one (P-gp) of the [9 major,10]. Drug mechanisms efflux medi- atedof byMDR ABC for transportersseveral classes has of beenanticancer identified drugs, as including one of theetoposide, major mechanismsDox, daunorubicin, of MDR for severalvincristine, classes vinblastine, of anticancer mitomycin drugs, C, including and mitoxantrone, etoposide, to Dox, name daunorubicin, a few [11–15]. vincristine,ABC vinblastine,transporters mitomycin are a largeC, family and of mitoxantrone, membrane channels to name that a regulate few [11– the15 ].movement ABC transporters of mol- are ecules of different sizes and chemical properties [16]. These transporters are found on the a large family of membrane channels that regulate the movement of molecules of different epithelial surface of various tissues, including brain, gastrointestinal tract, liver, renal tu- sizesbules, and adrenal chemical cortex, properties and placenta [16]. These[17]. They transporters play a crucial are foundrole in onthe theabsorption, epithelial distri- surface of variousbution, tissues, and excretion including of various brain, substances, gastrointestinal including tract, xenobiotics liver, renal and tubules, endogenous adrenal mol- cortex, andecules. placenta P-gp, [ 17which]. They is also play referred a crucial to as role MDR in theprotein-1 absorption, (MDR1 distribution,or ABCB1) is the and most excretion of variousstudied ABC substances, transporter including and associated xenobiotics with MDR and [12,18,19]. endogenous Two molecules. other ABC transport- P-gp, which is alsoers referred responsible to as for MDR MDR protein-1 in cancer (MDR1cells are orMDR-associated ABCB1) is the protein most studied1 (MRP1 ABCor ABCC1) transporter andand associated breast cancer with MDRresistance [12, 18protein,19]. Two(BCRP other or ABCABCG2) transporters [12,20,21]. responsibleP-gp is a dimeric for MDR in cancer cells are MDR-associated protein 1 (MRP1 or ABCC1) and breast cancer resistance protein (BCRP or ABCG2) [12,20,21]. P-gp is a dimeric membrane glycoprotein, and the two halves exhibit about 43% sequence homology. Both halves of P-gp form a highly hydrophobic transmembrane domain (TMD), which contains the substrate-binding region. A well-accepted mechanism of drug transport involves an inward opening of TMDs to allow substrate binding and, subsequently, an outward opening of the TMDs to release the substrate during the process of drug efflux. ATP binds to the cytoplasmic nucleotide-binding domain (NBD) and successively undergoes hydrolysis to provide the energy needed for the Cells 2021, 10, x FOR PEER REVIEW 3 of 16 membrane glycoprotein, and the two halves exhibit about 43% sequence homology. Both Cells 2021, 10, 458 halves of P-gp form a highly hydrophobic transmembrane domain (TMD), which contains 3 of 14 the substrate-binding region. A well-accepted

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