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Natural Products As Alternative Choices for P-Glycoprotein (P-Gp) Inhibition

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Natural Products As Alternative Choices for P-Glycoprotein (P-Gp) Inhibition molecules Review Natural Products as Alternative Choices for P-Glycoprotein (P-gp) Inhibition Saikat Dewanjee 1,*, Tarun K. Dua 1, Niloy Bhattacharjee 1, Anup Das 2, Moumita Gangopadhyay 3, Ritu Khanra 1, Swarnalata Joardar 1, Muhammad Riaz 4, Vincenzo De Feo 5,* and Muhammad Zia-Ul-Haq 6,* 1 Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Raja S C Mullick Road, Kolkata 700032, India; [email protected] (T.K.D.); [email protected] (N.B.); [email protected] (R.K.); [email protected] (S.J.) 2 Department of Pharmaceutical Technology, ADAMAS University, Barasat, Kolkata 700126, India; [email protected] 3 Department of Bioechnology, ADAMAS University, Barasat, Kolkata 700126, India; [email protected] 4 Department of Pharmacy, Shaheed Benazir Bhutto University, Sheringal 18050, Pakistan; [email protected] 5 Department of Pharmacy, Salerno University, Fisciano, 84084 Salerno, Italy 6 Environment Science Department, Lahore College for Women University, Jail Road, Lahore 54600, Pakistan * Correspondence: [email protected] (S.D.); [email protected] (V.D.F.); [email protected] (M.Z.-U.-H.) Academic Editor: Maria Emília de Sousa Received: 11 April 2017; Accepted: 15 May 2017; Published: 25 May 2017 Abstract: Multidrug resistance (MDR) is regarded as one of the bottlenecks of successful clinical treatment for numerous chemotherapeutic agents. Multiple key regulators are alleged to be responsible for MDR and making the treatment regimens ineffective. In this review, we discuss MDR in relation to P-glycoprotein (P-gp) and its down-regulation by natural bioactive molecules. P-gp, a unique ATP-dependent membrane transport protein, is one of those key regulators which are present in the lining of the colon, endothelial cells of the blood brain barrier (BBB), bile duct, adrenal gland, kidney tubules, small intestine, pancreatic ducts and in many other tissues like heart, lungs, spleen, skeletal muscles, etc. Due to its diverse tissue distribution, P-gp is a novel protective barrier to stop the intake of xenobiotics into the human body. Over-expression of P-gp leads to decreased intracellular accretion of many chemotherapeutic agents thus assisting in the development of MDR. Eventually, the effectiveness of these drugs is decreased. P-gp inhibitors act by altering intracellular ATP levels which are the source of energy and/or by affecting membrane contours to increase permeability. However, the use of synthetic inhibitors is known to cause serious toxicities. For this reason, the search for more potent and less toxic P-gp inhibitors of natural origin is underway. The present review aims to recapitulate the research findings on bioactive constituents of natural origin with P-gp inhibition characteristics. Natural bioactive constituents with P-gp modulating effects offer great potential for semi-synthetic modification to produce new scaffolds which could serve as valuable investigative tools to recognize the function of complex ABC transporters apart from evading the systemic toxicities shown by synthetic counterparts. Despite the many published scientific findings encompassing P-gp inhibitors, however, this article stand alones because it provides a vivid picture to the readers pertaining to Pgp inhibitors obtained from natural sources coupled with their mode of action and structures. It provides first-hand information to the scientists working in the field of drug discovery to further synthesise and discover new P-gp inhibitors with less toxicity and more efficacies. Keywords: P-glycoprotein (P-gp); multi drug resistance (MDR); ABC transporters; P-gp inhibitors; chemotherapy; xenobiotics Molecules 2017, 22, 871; doi:10.3390/molecules22060871 www.mdpi.com/journal/molecules Molecules 2017, 22, 871 2 of 93 1. Introduction Living organisms through constant evolution have developed defense mechanisms against Molecules 2017, 22, 871 2 of 107 persistent attacks from environmental toxins as it is necessary for them to avoid the pernicious effects1. of Introduction these cytotoxic compounds. Among the several defense mechanisms involved the one that pumpsLiving out toxic organisms substances through (through constant effluxevolution pumps) have developed from the intracellulardefense mechanisms space against of the cells is documentedpersistent both attacks in bacterial from environmental and mammalian toxins as cells.it is necessary Overexpression for them to avoid of these the pernicious pumps in effects cancer cells is a keyof regulator these cytotoxic of drug compounds. resistance Among during the several cancer defense chemotherapy. mechanisms involved In mammalian the one that cells, pumps this MDR phenotypeout toxic was substances first discovered (through ~40 efflux years pumps) ago, from by Ling the intracellular and co-workers space of [1 the]. cells is documented both in bacterial and mammalian cells. Overexpression of these pumps in cancer cells is a key Ling’s group noted that ovary cells of Chinese hamster that showed resistance to colchicine regulator of drug resistance during cancer chemotherapy. In mammalian cells, this MDR phenotype also displayedwas first discovered resistance ~40 towards years ago, a broad by Ling spectrum and co-workers of cytotoxic [1]. agents, however, very surprisingly the sharedLing’s little group or minimal noted that similarity ovary cells in of their Chinese chemical hamster structuresthat showed orresistance modes to of colchicine cytotoxicity also with colchicine.displayed This resistance phenomenon towards later a broad became spectrum known of cytotoxic as MDR. agents, Through however, molecular very surprisingly cloning the and shared functional characterizationlittle or minimal studies, similarity this resistantin their chemical phenotype structur wases or linked modes withof cytotoxicity a 170 kDa with surface colchicine. glycoprotein, This which theyphenomenon named later as permeability became known glycoproteinas MDR. Through (P-gp; molecular subfamily cloning B, and member functional 1: characterization ABCB1; also known studies, this resistant phenotype was linked with a 170 kDa surface glycoprotein, which they named as as MDR1)permeability for its capability glycoprotein to (P-gp; impede subfamily the cellular B, member permeability 1: ABCB1; also of known cytotoxic as MDR1) drugs for [ 2its]. capability Laterto impede on, it the was cellular understood permeability that of MDR1/P-gp cytotoxic drugs alone [2]. cannot be responsible for every type of MDR and this eventuallyLater on, it led was to understood the discovery that MDR1/P-gp of other related alone cannot transporters, be responsible especially for every breast type of cancer–resistance MDR and proteinthis (BCRP, eventually also knownled to the as discovery ABCG2) of and other MDR-associated related transporters, protein especially (MRP1 breast also cancer–resistance known as ABCC1). Aminoprotein acid sequence (BCRP, also analysis known as indicated ABCG2) and that MDR-a allssociated these MRPs protein comprise (MRP1 also multiple known as transmembrane ABCC1). Amino acid sequence analysis indicated that all these MRPs comprise multiple transmembrane domains (TMDs) and intracellularly confined ATP binding cassettes (ABCs) or nucleotide binding domains (TMDs) and intracellularly confined ATP binding cassettes (ABCs) or nucleotide binding domainsdomains (NBDs) (NBDs) (Figure (Figure1). 1). Figure 1. Basic structures of different types of P-gp transporters [2]. Figure 1. Basic structures of different types of P-gp transporters [2]. These transmembrane domains act as the channels whereby animal cells utilize the intracellularly Theseplaced transmembrane ABCs to hydrolyze domains ATP to provide act as the energy channels to expel whereby the cytotoxic animal drug cellss out through utilize theTMDs intracellularly thus placedreducing ABCs to intracellular hydrolyze drug ATP concentrations to provide energyto a sub-le tothal expel level. the The cytotoxic availability drugs of different out through types of TMDs ABC transporter proteins and the broad substrate specificity shown by these might explain the thus reducing intracellular drug concentrations to a sub-lethal level. The availability of different types complexity faced during the past couple of decades in attempting to thwart ABC-mediated MDR in of ABCvivo transporter. Although proteinsscientists andhave theworked broad hard substrate to develop specificity drugs that shown either impede by these the might function explain of the complexityefflux facedtransporters during or theevade past efflux, couple progress of decades in this area in has attempting been slow. to Inthwart spite of ABC-mediatedthis, the urge to MDR in vivo.understand Although the scientists underlying have principles worked involved hard in to MDR develop is still drugs strong thatand thorough either impede understanding the function of of efflux transportersthese transporters orevade is an absolute efflux, must progress to find in an this alternative area has to synthetic been slow. drugs In which spite are of frequently this, the urge to understandassociated theunderlying with systemic principles toxicity. involved in MDR is still strong and thorough understanding of Several protozoal parasites (Plasmodium, Leishmania, Trypanosoma) and some bacteria were observed these transportersto produce resistance is an absolute against must chemotherapeutic to find an alternative agents, such to syntheticas quinol drugsines, naphthoquinones,
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