ABC Drug Transporters as Molecular Targets for the Prevention of Multidrug Resistance and Drug-Drug Interactions

Calcagno, Anna Maria; Kim, In‐Wha; Wu, Chung-Pu; Shukla, Suneet; Ambudkar, Suresh V.

doi:10.2174/156720107782151241

Cited by 55 publications

(47 citation statements)

References 103 publications

(131 reference statements)

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“…In addition to P-gp, other ABC transporters may play a role in cancer cell chemoresistance (17,18). Our results indicate that nutlin-3 also interferes with MRP-1 activity.…”

Section: Discussionmentioning

confidence: 74%

Reversal of P-glycoprotein–Mediated Multidrug Resistance by the Murine Double Minute 2 Antagonist Nutlin-3

et al. 2009

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Murine double minute 2 (MDM2) negatively regulates the activity of the tumor suppressor protein p53. Nutlin-3 is a MDM2 inhibitor under preclinical investigation as nongenotoxic activator of the p53 pathway for cancer therapy. Here, nutlin-3 was evaluated for its activity alone or in combination with established chemotherapeutic drugs for antitumor action in chemosensitive and chemoresistant neuroblastoma and rhabdomyosarcoma cell lines. Effects of nutlin-3 single treatment were much more pronounced in p53 wild-type cell lines (IC 50 s <3 Mmol/L) than in p53-mutated cell lines (IC 50 s >17 Mmol/L). In sharp contrast to the expectations, nutlin-3 concentrations that did not affect viability of p53-mutated cell lines strongly increased the efficacy of vincristine in p53-mutated, P-glycoprotein (P-gp)-overexpressing cell lines (decrease in IC 50 s 92-to 3,434-fold). Similar results were obtained for other P-gp substrates. Moreover, nutlin-3 reduced efflux of rhodamine 123 and other fluorescence dyes that are effluxed by P-gp. Investigation of Madin-Darby canine kidney (MDCK) II cells stably transfected with plasmids encoding for P-gp (MDCKII MDR1) or multidrug resistance protein 1 (MRP-1, MDCKII MRP1) revealed that nutlin-3 not only interferes with P-gp but also affects MRP-1-mediated efflux. Kinetic studies and investigation of P-gp-ATPase activity showed that nutlin-3 is likely to act as a P-gp transport substrate. Examination of the nutlin-3 enantiomers nutlin-3a and nutlin-3b revealed that, in contrast to MDM2-inhibitory activity that is limited to nutlin-3a, both enantiomers similarly interfere with P-gp-mediated drug efflux. In conclusion, nutlin-3-induced inhibition of P-gp and MRP-1 was discovered as a novel anticancer mechanism of the substance in this report. [Cancer Res 2009;69(2):416-21]

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“…In addition to P-gp, other ABC transporters may play a role in cancer cell chemoresistance (17,18). Our results indicate that nutlin-3 also interferes with MRP-1 activity.…”

Section: Discussionmentioning

confidence: 74%

Reversal of P-glycoprotein–Mediated Multidrug Resistance by the Murine Double Minute 2 Antagonist Nutlin-3

et al. 2009

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“…These assays can be broadly classified into two categories: cell-based and membrane-based assays (Calcagno et al, 2007;Glavinas et al, 2008). In cell-based assays, transport of the candidate drug across the cell membrane is measured in a polarized monolayer using in vitro cultured cells.…”

Section: Introductionmentioning

confidence: 99%

“…Caco cells are the most popular for cell-based assays, because these cells can be grown in a monolayer that can be polarized for transport assays. Insect cells (High-Five, SF9), which can be grown in monolayers or in suspension cultures, are capable of overexpressing high levels of transporters for vesicular transport assays (Calcagno et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Use of Baculovirus BacMam Vectors for Expression of ABC Drug Transporters in Mammalian Cells

Shukla

Schwartz²,

Kapoor³

et al. 2012

Drug Metabolism and Disposition

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. These BacMam-baculovirus-transduced mammalian cells expressing Pgp or ABCG2 were used for assessing the functional activity of these transporters. Crude membranes isolated from these cells were further used to study the activity of these transporters by biochemical techniques such as photocross-linking with transport substrate and adenosine triphosphatase assays. In addition, we show that the BacMam expression system can be exploited to coexpress both Pgp and ABCG2 in mammalian cells to determine their contribution to the transport of a common anticancer drug substrate. Collectively, these data demonstrate that the BacMam-baculovirus-based expression system can be used to simultaneously study the transport function and biochemical properties of ABC transporters.

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“…It is well documented that transporters in the intestine, liver, kidney and brain are involved in the uptake and the efflux of chemical substances like food and drugs (Brandsch et al, 2008;Oostendorp et al, 2009;Rubio-Aliaga & Daniel, 2008;Zhou, 2008). The pharmacological effect and the disposition of drugs are thus highly influenced by the function of transporters located in specific tissues (Ayrton & Morgan, 2008;Calcagno et al, 2007;Türk & Szakács, 2009;Yuan et al, 2008). Evidence also supported the consequence of the involvement of transport proteins in the pharmacokinetic variability and the safety of drugs in human use (Tsuji, 2006).…”

Section: The Sites and The Mechanisms Of Xenobiotic-host Interactionmentioning

confidence: 99%

System Building For Safe Medication

Wang¹,

Lian²,

Wang³

2011

Risk Management Trends

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ABC Drug Transporters as Molecular Targets for the Prevention of Multidrug Resistance and Drug-Drug Interactions

Cited by 55 publications

References 103 publications

Reversal of P-glycoprotein–Mediated Multidrug Resistance by the Murine Double Minute 2 Antagonist Nutlin-3

Reversal of P-glycoprotein–Mediated Multidrug Resistance by the Murine Double Minute 2 Antagonist Nutlin-3

Use of Baculovirus BacMam Vectors for Expression of ABC Drug Transporters in Mammalian Cells

System Building For Safe Medication

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