Tricyclic isoxazoles are novel inhibitors of the multidrug resistance protein (MRP1)

Norman, Bryan H.; Gruber, Joseph M.; Hollinshead, Sean P.; Wilson, Joseph W.; Starling, James J.; Law, Kenneth S.; Self, Tracy D.; Tabas, Linda B.; Williams, Daniel C.; Paul, Donald C.; Wagner, M.; Dantzig, Anne H.

doi:10.1016/s0960-894x(02)00051-3

Cited by 50 publications

(35 citation statements)

References 10 publications

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“…A group of promising agents has been reported as potent MRP1-mediated MDR modulators by potentiating doxorubicin cytotoxicity, including LY-117018 and LY-329146, two raloxifene analogs [109,110], and LY-402913, an isoxazole derivate [111] (Fig. 5).…”

Section: Mrp Inhibitorsmentioning

confidence: 99%

Multidrug Resistance: Retrospect and Prospects in Anti-Cancer Drug Treatment

Pérez-Tomás¹

2006

CMC

466

323

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Conventional cancer chemotherapy is seriously limited by the multidrug resistance (MDR) commonly exhibited by tumour cells. One mechanism by which a living cell can achieve multiple resistances is via the active efflux of a broad range of anticancer drugs through the cellular membrane by MDR proteins. Such drugs are exported in both ATP-dependent and -independent manners, and can occur despite considerable concentration gradients. To the ATP-dependent group belongs the ATP-binding cassette (ABC) transporter family, which includes P-gp, MRP, BCRP, etc. Another protein related to MDR, though not belonging to the ABC transporter family, is lung resistance-related protein (LRP). All of these proteins are involved in diverse physiological processes, and are responsible for the uptake and efflux of a multitude of substances from cancer cells. Many inhibitors of MDR transporters have been identified over the years. Firstly, MDR drugs were not specifically developed for inhibiting MDR; in fact, they had other pharmacological properties, as well as a relatively low affinity for MDR transporters. They included compounds of diverse structure and function, such as verapamil and cyclosporine, and caused side effects. Secondly, the new drugs were more inhibitor-specific, in terms of MDR transport, and were designed to reduce such side effects (e.g., R-verapamil, dexniguldipine, etc.). Unfortunately, they displayed poor response in clinical studies. Recently, new compounds obtained from drug development programs conducted by the pharmaceutical industry are characterized by a high affinity to MDR transporters and are efficient at nanomolar concentrations. Some of these compounds (e.g., MS-209) are currently under clinical trials for specific forms of advanced cancers. We aim to provide an overview of the properties associated with those mammalian MDR transporters known to mediate significant transport of relevant drugs in cancer treatments. We also summarize recent advances concerning resistance to cancer drug therapies with respect to the function and overexpression of ABC and LRP multidrug transporters.

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Section: Mrp Inhibitorsmentioning

confidence: 99%

Multidrug Resistance: Retrospect and Prospects in Anti-Cancer Drug Treatment

Pérez-Tomás¹

2006

CMC

466

323

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“…[88][89][90][91][92][93] Among promising derivatives, LY402913 (Fig. 9) was identified as a potent MRP1-mediated MDR modulator, 94 by potentiating doxorubicin cytotoxicity in vitro and enhancing the antiproliferative activity of vincristine in vivo. In addition, it was evidenced that the modulator interacts with MRP1 as shown by its inhibition of MRP1-mediated LTC 4 transport into membrane vesicles.…”

Section: F Isoxazole-based Compoundsmentioning

confidence: 99%

Anticancer multidrug resistance mediated by MRP1: Recent advances in the discovery of reversal agents

Boumendjel

Baubichon‐Cortay

Trompier

et al. 2005

Medicinal Research Reviews

132

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Multidrug resistance protein 1 (MRP1) belongs to the ATP-binding cassette (ABC) transporter family. It is able to transport a broad range of anticancer drugs through cellular membranes, thus limiting their antiproliferative action. Since its discovery in 1992, MRP1 has been the most studied among MRP proteins, which now count nine members. Besides the biological work, which targets structure elucidation, binding sites location, and mode of action, most efforts have been focused on finding molecules which act as MRP1 inhibitors. In this review, we attempt to summarize and highlight studies dealing with modulators of MRP1-mediated multidrug resistance (MDR), which have been accomplished in the last 5 years. The reported MRP1 inhibitors are discussed according to their chemical class. Finally, we try to bring information on structure-activity relationship (SAR) aspects and how modulators might interact with MRP1. This study may facilitate the rational design of future modulators of MDR.

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“…They demonstrated that verapamil and trifluoropyrazin increase the cellular concentration of vincristine and vinblastine in resistant leukaemic cells in a mouse (Tsuruo et al 1981;Krishna & Mayer 2000). Since this discovery was made, the existence of numerous MDR-reversing agents has been reported (Barancı´k et al 2001;Kimura et al 2002;Norman et al 2002). Most of the chemosensitizers described until now may be divided into six groups according to their basic pharmacological activity (Ford 1996) (Table 3).…”

Section: Mdr Reversing By Pharmacological Modulationmentioning

confidence: 99%

A review of selected anti-tumour therapeutic agents and reasons for multidrug resistance occurrence

Sawicka

Kalinowska

Skierski

et al. 2004

Journal of Pharmacy and Pharmacology

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It is assumed that proteins from the ABC family (i.e., glycoprotein P (Pgp)) and a multidrug resistance associated protein (MRP) play a main role in the occurrence of multidrug resistance (MDR) in tumour cells. Other factors that influence the rise of MDR are mechanisms connected with change in the effectiveness of the glutathione cycle and with decrease in expression of topoisomerases I and II. The aim of this review is to characterize drugs applied in anti-tumour therapy and to describe the present state of knowledge concerning the mechanisms of MDR occurrence, as well as the pharmacological agents applied in reducing this phenomenon.

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Tricyclic isoxazoles are novel inhibitors of the multidrug resistance protein (MRP1)

Cited by 50 publications

References 10 publications

Multidrug Resistance: Retrospect and Prospects in Anti-Cancer Drug Treatment

Multidrug Resistance: Retrospect and Prospects in Anti-Cancer Drug Treatment

Anticancer multidrug resistance mediated by MRP1: Recent advances in the discovery of reversal agents

A review of selected anti-tumour therapeutic agents and reasons for multidrug resistance occurrence

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