Dissection of the Role of Multidrug Resistance Protein in Cancer

Lihan Xu

†

, Zhouchang Yao

†

and Enqian Zhu

†

School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin Campus, Panjin,124221, China

College of life science and technology, China Pharmaceutical University, Nanjing, 211198, China

School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China

†

These authors contributed equally

Keywords: Multidrug Resistance, Cancer.

Abstract: Cancer is a major public health problem worldwide, with the mortality estimated to grow for years, especially

with the belated access to care due to the pandemic of coronavirus disease 2019. Despite the emergence of

various oncology therapies during the past several decades, multi-drug resistance remains an important

challenge in cancer healing, especially in chemotherapies. This review includes the classification of

chemotherapeutic agents. As over 90% of mortalities in chemotherapies are caused by multi-drug resistance,

this study also elaborates the mechanisms of multi-drug resistance, with a deep insight into distinct types of

multidrug resistance proteins and the inhibitors related to them. The mechanisms of multidrug resistance

proteins are yet to be fully understood, and a few novel inhibitors of multidrug resistance proteins are still

under development. Thus, there are challenges for effective chemotherapies overcoming multi-drug

resistance. However, a few oncology treatments, such as immunotherapy and targeted drug delivery via DNA

nanostructure have weakened the impact of multi-drug resistance. The aim of this review is not only to

demonstrate the latest data on the studies of multi-drug resistance but also to offer information to those who

are searching for novel oncology therapies with higher cure rates, and plan to contribute to future multidrug

resistance studies as well as the emerging discoveries on mechanisms of MRPs.

1 INTRODUCTION

As a major public health problem worldwide, cancer

is a group of diseases. Several cells in the body grow

rapidly, spread beyond their boundaries, and invade

other parts of the body (National Cancer Institute

2007, WHO 2021). The mortality rate of cancer

increased in most of the 20th century until it peaked

in 1991. Then with the boom in the detection and

treatment of cancer, the mortality by 31% between

1991 and 2018, which means 3.2 million deaths

caused by cancer were prevented. Various cancer

therapies, including chemotherapy, surgery,

radiotherapy, immunotherapy, and biologically

targeted therapy, contribute to the effectiveness of

chemotherapy as the most common oncology

treatment (Bugde et al. 2017).

https://orcid.org/0000-0002-7445-7092

https://orcid.org/0000-0002-8561-6685

https://orcid.org/0000-0003-1769-2958

Either extracted from plants or synthetic

compounds, chemotherapeutics can be classified into

alkylating agents, topoisomerase inhibitors,

antimetabolites, mitotic spindle inhibitors, and others

according to the mechanism of action (Bukowski,

Kciuk, Kontek 2020). Alkylating agents can cause the

transfer of alkyl groups to the DNA guanine residues

or intra or inter-strand cross links, leading to DNA

base mispairing and the inhibition of strand

separation in the process of DNA synthesis

(Nussbaumer, Bonnabry, Veuthey, Fleury-Souverain

2011). Topoisomerase inhibitors include

topoisomerase I inhibitors (topotecan, irinotecan) and

topoisomerase II inhibitors(teniposide, etoposide,

doxorubicin, anthracyclines), both of which can lead

to DNA strand breakthrough manipulating

topoisomerases in DNA replication (Bax,

Murshudov, Maxwell, Germe 2019). Antimetabolites

Xu, L., Yao, Z. and Zhu, E.

Dissection of the Role of Multidrug Resistance Protein in Cancer.

DOI: 10.5220/0011254400003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 671-679

ISBN: 978-989-758-595-1

671

have interference in pathways of fundamental

biosynthesis, perturb the synthesis of DNA or RNA,

incorporate analogs of purine/pyrimidine with

different structures into DNA, or result in DNA

strand breaks by restraining a group of enzymes, for

instance, DNA polymerase, dihydrofolate reductase

(Marchi, O’Connor 2012). Mitotic spindle inhibitors

sustain activation of the spindle assembly checkpoint

(SAC), lengthening mitotic arrest, eventually

resulting in the cell's death. The entire inhibition

procedure is conducted in mitosis or in the G1 phase

of the following cell cycle (Sinha, Duijf, Khanna

2019). Besides the chemotherapeutic agents above,

other chemotherapeutic agents with distinct

mechanisms exist, for instance, tyrosine kinase

inhibitors, antibiotics, proteasome inhibitors, some

particular enzymes, including l-asparagincase, are

non-homogenous (Bukowski, Kciuk, Kontek 2020).

Figure 1: Classification of chemotherapeutics depending on their mechanism of action

However, the major challenge faced in cancer

chemotherapy is the less effective treatment due to

multidrug resistance (MDR), which remains the

second cause of death in developed countries (Garcia-

Mayea, Mir, Masson, Paciucci, LLeonart 2020).

MDR in oncology is defined as the ability of

resilience against drugs that are different in function

and structure. It was first discovered in experiments

with cultivated cells done by J.L. Biedler in 1970

(Biedler, Riehm 1970). Previous studies indicate that

multidrug resistance can appear before or during the

treatment, and it can be either acquired in the process

of chemotherapy or just inherent (Harris, Hochhauser

1992).

Mechanisms of MDR can be divided into several

categories: (1) promoted efflux of drugs by

transporters on the membrane of cancer cells, of

which ATP-binding cassette (ABC) transporters

function as main transporters (Chun, Kwon, Nam,

Kim 2015); (2) resistance to chemical substances

caused by microenvironment changes, for example,

cancer stem cell regulation (Li, Lei, Yao, et al. 2017);

(3) mutation in drug targets or feedback activation of

other targets and signaling pathways (Li, Lei, Yao, et

al. 2017); (4) decrease in drug uptake by influx

transporters; (5) promoted adaptability of cancer cells

enhanced by regulation of miRNA as well as

epigenetic regulation; (6) pathways of. apoptotic

signaling blocked as a result of altered level of B cell

lymphoma (BCL) family proteins expression or

mutant p53 pathway; (7) prompted metabolism of

xenobiotics (Bukowski, Kciuk, Kontek 2020).

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

672

MDR is most commonly led by the

overexpression of ABC, with a family of 49 human

membrane transporters involved in diverse

physiologic processes, in which P-glycoprotein (P-

gp), multidrug resistance-associated proteins

(MRPs), breast cancer resistance protein (BCRP) are

included (Liu 2019). P-glycoprotein (P-gp,

MDR1/ABCB1), as the first member of the ABC

transporter family, was found in drug-resistant

Chinese hamster ovary cells in 1976 by Victor Ling

functioning as an ATP binding cassette (ABC)

transporter (Juliano, Ling 1976). Experiments

indicate that the gene of P-gp, which was later

renamed ABCB1, can lead to drug resistance when

transfected into sensitive cells. Multidrug resistance-

associated protein 1 (MRP1/ABCC1), as the second

member of the ABC transporter family, discovered

by Cole et al. (Cole, Bhardwaj, Gerlach, et al. 1992),

can form resistance to vincristine etoposide,

doxorubicin (Mirski, Gerlach, Cole 1987). Different

from P-gp, which mainly transports hydrophobic

chemicals, the substrates of MRP1 and are

amphipathic organic acids with large hydrophobic

groups with a wide range of diversity in structure.

MRP1 also transports endobiotics, for instance,

hormones, pro-inflammatory molecules,

antioxidants, which P-gp doesn’t export (Kumar,

Jaitak 2019). Breast cancer resistance protein

(BCRP/ABCG2), as the third member of the ABC

transporter family, was first reported by Doyle et al.

in 1998, named from the drug selected breast cancer

cell line, i.e., MCF-7. Unlike P-gp or MRP1, both of

which are full transporters, BCRP is considered as the

shortest ABC transporter with one TMD and one

NBD. Through flocking by homodimerization or

heterodimerization with a disulfide bridge at Cys 603,

BCRP gains its full function (Kumar, Jaitak 2019).

2 MULTIDRUG RESISTANCE

PROTEINS (MRPS)

The ATP-binding cassette (ABC) transporters are

participants of a protein superfamily that are

recognized to transport intracellular and extracellular

materials, including metabolic products, lipids and

sterols, and xenobiotic drugs, and multidrug

resistance proteins (MRPs) belong to the largest

subfamily C in the ABC transporter superfamily

(Zhang, Wang, Gupta, Chen 2015). MRPs include

MRP1, MRP2 or cMOAT (the canalicular

multispecific organic anion transporter), MRP3,

MRP4 (cMOAT-B), MRP5 (cMOAT-C), MRP6,

MRP7, MRP8, and MRP9. The extended expression

of MRP is one of the integral motives of multidrug

resistance. MRPs have been implicated in mediating

multidrug resistance in tumor cells to many degrees

as the efflux extrude chemotherapeutic compounds

(or their metabolites) from malignant cells, so MRPs

are the groundwork for chemotherapeutic resistance

of many malignant tumors (Chen, Tiwari 2011).

2.1 Multidrug Resistance Protein 1

(MRP1)

MRP1(ABCC1) was once discovered in 1992, the

predominant member of the MRP subfamily-

associated MDR (Ma, Hu, Wang, et al. 2014). The

MRP1 gene is positioned in the lengthy arm 13.1

bands of human chromosome 16 with a molecular

weight of 190 kDa. The structure of MRP1 consists

of two transmembrane domains (TMD) and two

nucleotide-binding domains (NBD), and an extra N-

terminal TMD-TMD0, in which TMD is accountable

for substrate recognition, binding, and transport. At

the same time, NBD is concerned with ATP binding

and hydrolysis to grant strength for transport

(Johnson, Chen 2017). MRP1 transports a range of

therapeutic agents as properly as a variety of

physiological substrates. It may also play a role in

improving drug resistance in a range of cancers,

including lung cancer, breast cancer, persistent

lymphocytic leukemia, acute lymphocytic leukemia,

prostate cancer, and pediatric neuroblastoma (Munoz,

Henderson, Haber, Norris 2007). MRP1 is expressed

in the liver, kidney, intestine, brain, and other tissues,

transporting structurally numerous necessary

endogenous substances (e.g., leukotriene and

conjugated estrogen) and heterogeneous biological

and their metabolites, such as a number conjugates,

anti-cancer drugs, heavy metals, organic anion, and

lipids, with features concerned in inflammation,

detoxification, and oxidative stress (Nasr, Lorendeau,

Khonkarn, et al. 2020, He, Li, Kanwar, Zhou 2011).

2.2 Multidrug Resistance Protein 2

(MRP2)

ABCC2 encodes MRP2, which was once first

identified and cloned from rat liver cells. MRP2 not

only exists in tumor cells but also in the small

intestine, liver, kidney, placental barrier, and blood-

brain barrier (Zhang, Wang, Gupta, Chen 2015,

ostendorp, Beijnen, Schellens 2009). Similar to

MRP1, MRP2 has two MSDs characteristic of ABC

transporters, in addition to a third NH2-terminal MSD

(MSD0) and a COOH-terminal region. Sequences

Dissection of the Role of Multidrug Resistance Protein in Cancer

673

inside MSD0 of MRP2 are required for its activity and

plasma membrane trafficking, as are sequences within

its COOH terminal region (Chen, Tiwari 2011).

MRP2 promotes the excretion of drugs and chemicals,

especially MRP2 mediates ATP-dependent outflow of

various drugs and chemical compounds (including

glucosidic acid, sulfate, and glutathione complexes),

so drugs and chemical substances can be eliminated

from cells (Wen, Joy, Aleksunes 2017).

2.3 Multidrug Resistance Protein 3

(MRP3)

The amino acid sequence homology of MRP3 and

MRP1 is the highest, about 58%. MRP3 used to be

often positioned in the basement membrane of

hepatocytes and more often than expressed in the

adrenal gland, kidney, small intestine, colon,

pancreas, and gallbladder. However, the expression

stage of MRP3 was once low in the lung, spleen,

stomach, and tonsil (Zhang, Wang, Gupta, Chen

2015, Chen, Tiwari 2011). One of the features of

MRP3 is to mediate the transport of anionic

complexes and optimize the endogenous lipophilic

substances, exogenous resources, and glycosides of

bile sulfate. At the same time, it can also preserve the

stability of bile acid metabolism and adjust the

transport of soluble compounds in bile (Pérez-Pineda,

Baylón-Pacheco, Espíritu-Gordillo, Tsutsumi,

Rosales-Encina 2021).

2.4 Multidrug Resistance Protein 4

(MRP4)

MRP4 (ABCC4) was first discovered in human T

lymphoid cell lines in 1999. MRP4 is a vast substrate-

specific carrier, dispensed in nearly all tissues and

cells, inclusive of lung, ovary, testis, kidney,

intestine, liver, brain, pancreas, prostate, and more

than a few blood cells, and expressed in a range of

human tissues (examples are the basolateral and

apical plasma membranes from the liver and kidneys)

(Pérez-Pineda, Baylón-Pacheco, Espíritu-Gordillo,

Tsutsumi, Rosales-Encina 2021). MRP4 (MOAT-B)

is a lipophilic anion efflux pump capable of

conferring resistance to huge varying from substrates,

including nucleotide analogs, MTX, and glutathione

(GSH). Compared with other transgenic egg whites,

ABCC4 has a typical ABC transporter core structure,

specifically two transmembrane domains and two

nucleotide-binding domains (Zhang, Wang, Gupta,

Chen 2015). MRP4 is a plausible therapeutic target

for MDR. MRP4 was once noticeably expressed in

myeloid progenitors, and various endogenous

molecules are transported out of cells. MRP4 protects

cell function through 6-mercaptopurine (6-MP)

efflux. However, it can make most cancer cells

resistant to anticancer drugs and limit the sensitivity

of the tumor to radiotherapy and chemotherapy (Ma,

Hu, Wang, et al. 2014).

3 INHIBITORS

3.1 MRP1 Inhibitor - Sulindac

Sulindac appears to have favourable characteristics as

a potential MRP-1 inhibitor since in vitro inhibition

is evident at concentrations achievable in serum with

standard doses of the agent. Also, sulindac is

relatively nontoxic and well-tolerated because of the

small number of NSAIDs that might be used,

especially when used in an acute setting. The primary

biological metabolites and certain analogues of it

have been demonstrated to have pro-apoptotic

actions. Sulindac potentially inhibition of MRP-1-

mediated doxorubicin resistance coupled with other

activities such as anti-angiogenesis, which has been

described for sulindac and led to a potentiation of the

toxicity of doxorubicin without using toxic

concentrations. Also, sulindac is able to potentiate the

anti-tumour activity of doxorubicin in some animal

models (Anticancer Research 2004).

3.2 MRP1 and MRP2

Inhibitor - Nonsymmetrical 1,

4-Dihydropyridines

It is non-symmetrical compounds that have been

investigated to inhibit MRP1 and MRP2, both with a

non-symmetric framework. It is developed by novel

non-symmetrically substituted 1,4-dihydropyridines

in a different approach than the known so-called one-

pot reaction. The reaction mixture consists of the

afore-described three compounds to result in the

molecular 1,4-dihydropyridine scaffold.

Nonsymmetrical 1,4-Dihydropyridines express

MRP1 and MRP2 using the fluorescent

carboxyfluorescein diacetate (CFDA) as MRP

substrate. The respective cells were pre-incubated

with the potential inhibitors, and then the fluorescent

substrate was added. The substrate uptake was

measured by flow cytometry detecting the

corresponding fluorescence of the respective cells.

The fluorescence was related to the untreated control

cells measured to give a fluorescence activity ratio

(FAR) value (Pharmaceuticals 2020).

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674

3.3 MRP3 and MRP4

Inhibitor - CG200745

CG200745, (E)- N(1)-(3-(dimethylamino)propyl)-

N(8)-hydroxy-2-((naphthalene-1-loxy) methyl) oct-2-

enediamide, is a recently developed HDAC inhibitor.

As a novel, HDAC inhibitor, CG200745, is an

intravenous hydroxamate-based pan-HDAC inhibitor.

Its inhibitory effect on cell growth has been

demonstrated in several types of cancer cells,

including prostate cancer, renal cell carcinoma, and

colon cancer in mono- and combinational-therapy

with other anticancer drugs. CG200745 was well

tolerated at the tested doses with no dose-limiting

toxicities in the first human study. The effect of

CG200745 on pancreatic cancer cell apoptosis was

tested by Western blot analysis, which indicated that

CG200745 increased the expression of pro-apoptotic

proteins, BAX, and p21. CG200745 induced the

expression of apoptotic proteins (PARP and caspase-

3) and increased the levels of acetylated histone H3.

CG200745 with gemcitabine/erlotinib showed

significant growth inhibition and synergistic

antitumor effects in vitro. In vivo,

gemcitabine/erlotinib and CG200745 reduced tumor

size up to 50%. CG200745 enhanced the sensitivity of

gemcitabine-resistant pancreatic cancer cells to

gemcitabine and decreased the level of ATP-binding

cassette-transporter genes, especially MRP3 and

MRP4. The novel HDAC inhibitor, CG200745, with

gemcitabine/erlotinib, had a synergistic anti-tumor

effect on pancreatic cancer cells. CG200745

significantly improved pancreatic cancer sensitivity to

gemcitabine, with a prominent antitumor effect on

gemcitabine-resistant pancreatic cancer cells

(Scientific Reports 2017).

3.4 MRP4 Inhibitor - MK-571

MK571 is a multidrug resistance protein-1, multidrug

resistance protein-2, and multidrug resistance

protein-4 (MRP1, MRP2, and MRP4) inhibitor. It has

been widely used to demonstrate the role of Mrp2 in

the cellular efflux of drugs, xenobiotics, and their

conjugates. Increasing the dosing concentration of

MK-571 in the in vivo study is restricted by its

solubility. Higher exposure of MK-571 in blood cells

and tissues may increase the intracellular

concentration of Methotrexate caused by MRP4

inhibition. MK-571 was selected as the concomitant

drug possessing inhibitory potency for MRP

transporters, demonstrating a typical bile-excretion

pharmacokinetic property. It is efficient in inhibiting

MRP1, MRP2, and MRP4 in cancer therapy (etm

2012).

Suppressing drug efflux is an important aim in

many drug development programs, so as in cancer

therapy. Chemically modifying or redesigning an

anticancer drug to completely bypass MRPs is

challenging. But no specific rules have been found,

as they can recognize diverse structures that permeate

cellular membranes. At the same time, modifications

of an anticancer drug without diminution of drug

potency are much harder. In comparison, drug

delivery systems offer seemingly innumerable

possibilities and provide the potential for safer and

high-dose delivery of anticancer drugs while using

noninvasive tracking techniques that are target-

specific. In these cases, controlling drug release

inside the cells could be significant, and the

exploration of inhibitors is of great importance for

our future.

a: MRP1 and MRP2 inhibitor - Nonsymmetrical 1,4-Dihydropyridines

b: MRP1 inhibitor -Sulindac

c: MRP3 and MRP4 inhibitor -CG200745

d: MRP4 inhibitor - MK-571

Figure 2. The structure of inhibitors.

Dissection of the Role of Multidrug Resistance Protein in Cancer

675

Table 1: Structure and function of MRPs and related inhibitors (NR: not report).

MRPs Chromosomal

localization

Exon

coding

Amino

acids

Physiological

function

major drugs substrate

inhibitors

Reference

MRP1 6p13.11-13 31 1531 Maintain the

dynamic

balance of GSH

in vivo and

protect cells

from the toxic

damage of

bilirubin

amycin,

vincristine,

etoposicIe,

Methotrexate,

camptothec,

Irinotecan, and

its active

metabolites SN-

38,

cyclophosphami

diphenylsulfami

de, benzazolone,

Indometacin,

Verapamil,

quercetin,

Genistein,

cyclosporin A,

steroids,

glibenpiride,

Glucovance

(Bakos,

Homolya 2007,

Wei, Sun, Liu

2010)

MRP2 10q23-24 32 1541 Transport of

hydrophobic,

uncharged

molecules or

water-soluble

anionic

compounds

cisplatin,

etoposicIe,

Vinblastine,

camptothec,

Methotrexate,

Olmesartan,

lopinovi

furosemide (Kruh,

Belinsky, Gallo,

Lee 2007)

MRP3 17q21.3 31 1527 Transport bile

salts and various

organic acids,

E217βG can be

transported

efficiently

etoposicIe,

acetaminophen,

glucuronic acid

glycosides,

vincristine,

Methotrexate

etoposicIe,

Methotrexate

(Chu, Huskey,

Braun, Sarkadi,

Evans, Evers

2004)

MRP4 13q32.1 31 1325 It plays a key

role in the

protection of

cells and cell

signaling

pathways by

regulating the

redistribution

and excretion of

various

inhibitory cell

growth drugs,

antiviral drugs,

antibiotics, and

cardiovascular

drugs in vivo

and in the

kidney

Methotrexate, 6-

mercaptopurine

,6-thioguanine,

Adefovir,

topotecan

celecoxib,

rofecoxib,

diclofenac

(Russel,

Koenderink,

Masereeuw

2008)

MRP5 3q27 NR 1437 It mediates the

signal

transduction

process of

biological cells

and binds GSH

and its

compounds and

even heavy

metals

mercaptopurine,

6-thioguanine,

Adefovir, heavy

metals, S-GSH

Diprophenyl

sulfamide,

sulphinpyrazone

benzbromarone,

(Homolya,

Váradi, Sarkadi

2003)

MRP6 16p13.1 31 1503 S-conjugated

GSH transport

is associated

with pulmonary

elastic fibrosis

leukotriene

C4(LTC4), N-

hexyl cis-butene

diimide, S-GSH,

dinitrophenol,

podophylloside,

doxorubicin,

cisplatin,

Daunorubicin

Indometacin,

disulfonamide,

Benzbromarone

(Hendig,

Langmann,

Kocken, et al.

2008)

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

676

MRP7 6p12-21 22 1492 Modulate the

transport effects

of E217βG

17-β-D-

glucuronside,

paclitaxel,

Vinblastine,

SN-38, amycin,

carboplatin

imatinib

(Chen, Hopper-

Borge, Belinsky,

Shchavelev,

Kotova, Kruh

2003)

MRP8 16q12.1 28 1382 Transport of

nucleotides,

transport of

glycocholate

and taurocholate

5-FU, Adefovir,

Methotrexate,

Chile Acid

NR (Che, Guo,

Belinsky,

Kotova, Kruh

2005)

MRP9 16q12.1 29 1359 Transport

nucleotides,

immune

markers of

reast cance

NR NR (Zhou, Wang,

Di, et al. 2008)

4 CONCLUSIONS

This paper reviews the status and trend of research of

the last five years based on the papers published in

major educational technology journals. In summary,

this paper shows that:

 the current status of cancer epidemiology with

the pandemic of COVID-19;Bottom: 4,2 cm;

 the oncology treatments correlated to

multidrug resistance; Right: 2,6 cm.

 molecular mechanism of multidrug resistance

 the classification and insight of multidrug

resistance protein; Bottom: 4,2 cm;

 the definition, physicochemical property, and

function of MRPs inhibitors. Right: 2,6 cm.

Due to the coronavirus disease 2019 (COVID-19)

pandemic, the situation of oncology treatment in

2020 was relatively distinct. A short-term decrement

in cancer incidence is followed by the growth in

advanced-stage disease, causing increased mortality,

resulting from delays in diagnosis and treatment

caused by unavailable or belated access to care.

Unfortunately, the consequence of COVID-19 is

estimated to last for years to qualify, which burdens

cancer therapy, even more, making effective tumor

treatments of significance. The findings included in

this paper could be good references for those

searching for novel oncology therapies with higher

cure rates, and plan to contribute to future multidrug

resistance studies and the emerging discoveries on

mechanisms of MRPs. In addition, the insight could

be helpful to future researches on inhibitors of MRPs

as well.

However, provided with cancer treatments in

existence, multidrug resistance can be avoided in

immunotherapy, or weakened by targeted drug

delivery via DNA nanostructure.

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