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Multidrug resistance in cancer: role of ATP–dependent transporters

Key Points

  • Multidrug resistance of cancer cells is a potentially surmountable obstacle to effective chemotherapy of cancer.

  • ATP-binding cassette (ABC) transporters, including MDR1 (ABCB1), MRP1 (ABCC1) and ABCG2, can confer multidrug resistance to cancer cells in vitro.

  • MRP2 (ABCC2), MRP3 (ABCC3), MRP4 (ABCC4), MRP5 (ABCC5), ABCA2 and BSEP (ABCB11) are capable of transporting drugs; future studies are needed to determine a role in drug resistance.

  • ABC transporters such as MDR1 and MRP1 are expressed in many human cancers, including leukaemias and some solid tumours; in some studies, expression of these transporters has been shown to correlate with response to therapy and survival.

  • Inhibitors of ABC transporters such as MDR1/P-glycoprotein have been tested in clinical trials with a suggestion of benefit, especially in acute myelogenous leukaemia.

  • Interpretation of clinical trials using inhibitors of MDR1/P-glycoprotein has been confounded by their effects on the pharmacokinetics of anticancer drugs.

  • Development of inhibitors of ABC transporters should focus on potency and specificity to minimize unexpected pharmacokinetic effects.

  • Efficacy should be confirmed using surrogate assays.

  • Normal tissues might be protected from toxicity by gene transfer of drug-resistance genes.

  • Prevention of ABC transporter induction in cancer cells might help to avert drug resistance.

Abstract

Chemotherapeutics are the most effective treatment for metastatic tumours. However, the ability of cancer cells to become simultaneously resistant to different drugs — a trait known as multidrug resistance — remains a significant impediment to successful chemotherapy. Three decades of multidrug-resistance research have identified a myriad of ways in which cancer cells can elude chemotherapy, and it has become apparent that resistance exists against every effective drug, even our newest agents. Therefore, the ability to predict and circumvent drug resistance is likely to improve chemotherapy.

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Figure 1: Cellular factors that cause drug resistance.
Figure 2: Structures of ABC transporters known to confer drug resistance.
Figure 3: A surrogate assay for PGP inhibition.
Figure 4: 99mTc-sestamibi imaging to monitor PGP activity.

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Correspondence to Michael M. Gottesman.

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DATABASES

CancerNet:

acute myelogenous leukaemia

adrenocortical cancer

breast tumours

chronic lymphocytic leukaemia

colon cancer

hepatocellular cancer

kidney cancer

non-small-cell lung cancers

oesophageal carcinoma

osteosarcomas

soft-tissue sarcomas

 LocusLink:

ABCA2

ABCB1

ABCG2

BSEP

cytochrome P450

Mdr1a

Mdr1b

MDR3

Mrp1

MRP1

Mrp2

MRP2

MRP3

MRP6

p53

SXR

 Medscape DrugInfo:

amiodarone

cisplatin

cyclosporin A

daunorubicin

docetaxel

doxorubicin

etoposide

5-fluorouracil

methotrexate

mitoxantrone

nifedipine

paclitaxel

progesterone

quinidine

quinine

tamoxifen

verapamil

vinblastine

vincristine

 OMIM:

Dubin–Johnson syndrome

progressive familial intrahepatic cholestasis type-3

FURTHER INFORMATION

Breast Cancer Drug Resistance Database

The Center for Adaptation Genetics and Drug Resistance

Glossary

MULTIDRUG RESISTANCE

Simultaneous resistance to several structurally unrelated drugs that do not have a common mechanism of action.

VINCA ALKALOIDS

A family of natural-product anticancer drugs, extracted from the periwinkle family, that depolymerize microtubules. Examples include vincristine and vinblastine.

ANTHRACYCLINES

Semi-synthetic anticancer derivatives of anthraquinone that intercalate into DNA and inhibit DNA topoisomerase II. Examples include daunorubicin and doxorubicin.

CYTOCHROME P450

A group of enzymes that are located on the endoplasmic reticulum, and are involved in drug metabolism and detoxification. They are primarily expressed in the liver and small intestine.

MULTIFACTORIAL MULTIDRUG RESISTANCE

Multidrug resistance caused by several different mechanisms of resistance that operate simultaneously.

FLIPPASE

A transport system that moves substrates from one leaflet of the membrane bilayer to the other leaflet.

BILIRUBIN

A breakdown product of haemoglobin that is processed by the liver, where it is conjugated to glucuronic acid and excreted in the bile. Accumulation of bilirubin in the blood and tissues can lead to jaundice and neurological damage.

CANALICULAR MEMBRANES

Surface of the hepatocyte that faces the biliary canaliculus, through which bile is excreted.

MYELOSUPPRESSION

Temporary inhibition of bone-marrow production, caused by chemotherapy-mediated cytotoxicity to blood-cell precursors.

TAXANES

A family of natural-product and semi-synthetic agents, including paclitaxel, which was originally isolated from the bark of the yew tree. Their mechanism of action includes stabilization of microtubules and inhibition of mitosis.

CEREBELLAR ATAXIA

Difficulty in walking caused by impaired cerebellar function.

MYELODYSPLASTIC SYNDROME

A disorder of haematopoietic cells that often leads to acute leukaemia.

CD56+ CELLS

A subset of circulating lymphocytes, known as natural killer cells, that express the CD56 antigen. They are used to test drug effectiveness in clinical studies because they express high levels of MDR1/P-glycoprotein.

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Gottesman, M., Fojo, T. & Bates, S. Multidrug resistance in cancer: role of ATP–dependent transporters. Nat Rev Cancer 2, 48–58 (2002). https://doi.org/10.1038/nrc706

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