Elsevier

Advanced Drug Delivery Reviews

Volume 62, Issue 13, 30 October 2010, Pages 1257-1264
Advanced Drug Delivery Reviews

Overcoming drug resistance by regulating nuclear receptors

https://doi.org/10.1016/j.addr.2010.07.008Get rights and content

Abstract

Drug resistance involves multiple mechanisms. Multidrug resistance (MDR) is the leading cause of treatment failure in cancer therapy. Elevated levels of MDR proteins [members of the ATP-binding cassette (ABC) transporter family] increase cellular efflux and decrease the effectiveness of chemotherapeutic agents. As a salvage approach to overcome drug resistance, inhibitors of MDR proteins have been developed, but have had limited success mainly due to undesired toxicities. Nuclear receptors (NRs), including pregnane X receptor (PXR), regulate the expression of proteins (including MDR proteins) involved in drug metabolism and drug clearance, suggesting that it is possible to overcome drug resistance by regulating NR. This review discusses the progress in the development of MDR inhibitors, with a focus on MDR1 inhibitors. Recent development of PXR antagonists to pharmacologically modulate PXR is also reviewed. The review proposes that selectively preventing the elevation of MDR levels by regulating NRs rather than non-selectively inhibiting the MDR activity by using MDR inhibitors can be a less toxic approach to overcome drug resistance during cancer therapy.

Introduction

Drug resistance — the reduction in effectiveness of a drug in curing a disease or improving patient symptoms — can develop against antibiotics, antivirals, or chemotherapeutic agents for cancers. Drug resistance is a complex cellular response and target-specific and target-nonspecific mechanisms can be involved in the process.

In target-specific drug resistance, changes in a specific drug target that decrease the interaction between the target and drug might lead to drug resistance. For example, mutations in viral genes frequently lead to antiviral drug resistance [1], and loss of expression of the estrogen receptor (ER) can cause tamoxifen resistance in patients with breast cancer [2]. It can be difficult to predict, prevent, or overcome target-specific drug resistance without developing new therapeutic agents. On the other hand, in target-nonspecific drug resistance, changes in parameters not directly relevant to or dependent on the drug target contribute to drug resistance. For example, target cells or organisms might produce higher levels of drug-metabolizing enzymes (DMEs) to degrade the drug or increase their efflux capacity, resulting in decreased bioavailability and reduced effectiveness of drug [3].

Cases of target-nonspecific drug resistance have several features in common, which have been targeted by various approaches in order to overcome drug resistance, especially against chemotherapeutic agents. For example, a family of ATP-dependent drug pumps, known as ATP-binding cassette (ABC) transporter proteins, can increase the resistance to chemotherapeutic agents by increasing cellular efflux. Multidrug resistance (MDR) proteins belong to the ABC transporter protein family and play an important role in maintaining normal physiologic functions that protect human tissues from drugs and other xenobiotics. Elevated levels of MDR1, a key MDR protein [also known as P-glycoprotein (P-gp) or ABCB1], have been associated with drug-mediated drug resistance in cancer [4], making inhibition of MDR1 activity a logical approach to overcome MDR1-mediated drug resistance.

This review discusses the progress made in the development of MDR1 inhibitors in overcoming drug resistance in cancer. As the primary role of MDR1 is disposition of xenobiotics, the undesired toxicities resulting from the use of MDR1 inhibitors have posed a challenge in the development of MDR1 inhibitors for clinical applications. The problems encountered and the lessons learned in developing MDR1 inhibitors as salvage therapies to reverse drug resistance are reviewed.

The expression of MDR1 as well as other proteins involved in regulating the bioavailability of drugs is regulated by nuclear receptors (NRs), a family of ligand-activated transcription factors. The pregnane X receptor (PXR) is an NR that directly regulates the expression of MDR1 and other important proteins involved in drug metabolism and resistance. PXR can be activated by xenobiotics, including drugs involved in MDR, suggesting that drug resistance can be prevented instead of being reversed. The recent progress made in developing PXR antagonists to pharmacologically modulate PXR and thereby potentially prevent the elevation of MDR1 levels is also reviewed.

Recently, a new form of MDR — drug ratio-dependent MDR — has been reported in cancer therapy, which occurs at discrete drug:drug ratios of combined chemotherapeutic agents. Drug ratio-dependent MDR can be circumvented by systematically screening a wide range of drug ratios and concentrations and encapsulating the drug combination in a liposomal delivery vehicle at optimal synergistic ratios. This has been recently reviewed [5], and will not be discussed here.

Section snippets

Cancer and drug resistance

Despite years of intensive research and development, cancer remains one of the leading causes of death worldwide. In 2009, there were an estimated 1.5 million new cases of and 560,000 deaths from cancer in the US [6]. Chemotherapy is the most commonly used treatment for cancer, as surgery and radiation are often not effective in treating cancer at every location where it spreads. MDR of cancer cells to chemotherapeutic agents — a complex cellular process — is the leading cause of failure of

Regulation of drug resistance by nuclear receptors

MDR1, MRP1, and BCRP — the ABC transporters that mediate the ATP-dependent cellular export of drugs — have high expression levels in liver, intestine, kidney, and blood-brain barrier. Their normal physiologic function is to protect the body from cytotoxicity caused by drugs or other xenobiotics. This protecting function is coordinated with the DMEs, which first break down the drugs in most cases. MDR1, MRP1, and BCRP, which partially overlap in their substrate specificity, are the major ABC

Conclusions

Drug resistance involves multiple mechanisms and targets; it is therefore impossible to overcome drug resistance by targeting a single protein. MDR1 is an important protein involved in target-nonspecific drug resistance. Inhibition of MDR1 to overcome drug resistance has had limited success due to toxicity. MDR1 expression can be regulated by several mechanisms. The recent discovery that the expression of MDR1 is induced by PXR, a xenobiotic receptor activated by many compounds, including

Acknowledgements

I thank Drs. Wenwei Lin, Satya Pondugula, Su Sien Ong, Yueming Wang and other members of the Chen research laboratory for their valuable discussions, and Dr. Vani Shanker for editing the manuscript. This work was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grant GM086415] (to T.C.); the National Institutes of Health National Cancer Institute [Grant P30-CA027165]; the American Lebanese Syrian Associated Charities; and St. Jude Children's

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    This review is part of the Advanced Drug Delivery Reviews theme issue on “Development of Novel Therapeutic Strategy by Regulating the Nuclear Hormone Receptors”.

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