Inhibiting drug efflux transporters improves efficacy of <scp>ALS</scp> therapeutics

Jablonski, Michael; Markandaiah, Shashirekha S.; Jacob, Dena A.; Meng, Ni J.; Li, Ké; Gennaro, Victoria; Lepore, Angelo C.; Trotti, Davide; Pasinelli, Piera

doi:10.1002/acn3.141

Cited by 83 publications

(90 citation statements)

References 37 publications

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“…Recently, it was shown that the amyotrophic lateral sclerosis (ALS) drug riluzole has increased efficacy in an animal model of familial ALS when co-administered with an ABC transporter inhibitor elacridar (Jablonski et al, 2014). Additionally, co-administration of tariquidar with the anti-seizure drug pentobarbital improves anti-epileptic activity in previously drug resistant rats (Brandt et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

CNS uptake of bortezomib is enhanced by P-glycoprotein inhibition: implications for spinal muscular atrophy

Foran

Kwon

Nofziger

et al. 2016

Neurobiology of Disease

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The development of therapeutics for neurological disorders is constrained by limited access to the central nervous system (CNS). ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are expressed on the luminal surface of capillaries in the CNS and transport drugs out of the endothelium back into the blood against the concentration gradient. Survival motor neuron (SMN) protein, which is deficient in spinal muscular atrophy (SMA), is a target of the ubiquitin proteasome system. Inhibiting the proteasome in a rodent model of SMA with bortezomib increases SMN protein levels in peripheral tissues but not the CNS, because bortezomib has poor CNS penetrance. We sought to determine if we could inhibit SMN degradation in the CNS of SMA mice with a combination of bortezomib and the ABC transporter inhibitor tariquidar. In cultured cells we show that bortezomib is a substrate of P-gp. Mass spectrometry analysis demonstrated that intraperitoneal co-administration of tariquidar increased the CNS penetrance of bortezomib, and reduced proteasome activity in the brain and spinal cord. This correlated with increased SMN protein levels and improved survival and motor function of SMA mice. These findings show that CNS penetrance of treatment for this neurological disorder can be improved by inhibiting drug efflux at the blood-brain barrier.

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Section: Discussionmentioning

confidence: 99%

CNS uptake of bortezomib is enhanced by P-glycoprotein inhibition: implications for spinal muscular atrophy

Foran

Kwon

Nofziger

et al. 2016

Neurobiology of Disease

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“…A likely culprit underlying the limited effectiveness of riluzole, the only FDA-approved drug for ALS treatment, is the multidrug efflux transporter ABCB1 or P-glycoprotein (P-gp) (Jablonski et al, 2015; Jablonski et al, 2014). P-gp is a membrane-bound protein that works to expel substances out of cells, and is expressed on the apical membrane (blood side) of endothelial cells, which comprise the functional core of the blood-brain barrier (BBB) and blood spinal cord barrier (BSCB) (Abbott et al, 2010; Wong et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…These results, together with evidence that riluzole is a P-gp substrate (Milane et al, 2007), suggested that riluzole’s limited efficacy could, at least partially, result from P-gp driven pharmacoresistance that develops over the course of the disease. In a recent proof-of-principle study using SOD1-G93A ALS mice, we showed that co-administration of elacridar, a selective P-gp inhibitor, increased riluzole therapeutic efficacy (Jablonski et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

Astrocytes drive upregulation of the multidrug resistance transporter ABCB1 (P‐Glycoprotein) in endothelial cells of the blood–brain barrier in mutant superoxide dismutase 1‐linked amyotrophic lateral sclerosis

Qosa

Lichter

Sarlo

et al. 2016

Glia

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The efficacy of drugs targeting the CNS is influenced by their limited brain access, which can lead to complete pharmacoresistance. We recently reported a tissue-specific and selective upregulation of the multidrug efflux transporter ABCB1 or P-glycoprotein (P-gp) in the spinal cord of both patients and the mutant SOD1-G93A mouse model of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease that prevalently kills motor neurons. Here, we have extended the analysis of P-gp expression in the SOD1-G93A ALS mouse model and found that P-gp upregulation was restricted to endothelial cells of the capillaries, while P-gp expression was not detected in other cells of the spinal cord parenchyma such as astrocytes, oligodendrocytes, and neurons. Using both in vitro human and mouse models of the blood-brain barrier (BBB), we found that mutant SOD1 astrocytes were driving P-gp upregulation in endothelial cells. In addition, we observed a significant increase in reactive oxygen species production, Nrf2 and NFκB activation in endothelial cells exposed to mutant SOD1 astrocytes in both human and murine BBB models. Most interestingly, astrocytes expressing FUS-H517Q, a different familial ALS-linked mutated gene, also drove NFκB-dependent upregulation of P-gp. However, the pathway was not dependent on oxidative stress but rather involved TNFα release. Overall, our findings indicate that nuclear translocation of NFκB is a converging mechanism used by endothelial cells of the BBB to upregulate P-gp expression in mutant SOD1-linked ALS and possibly other forms of familial ALS.

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“…Additionally, the only current FDA-approved drug for ALS management, riluzole, is suggested to be a P-gp and BCRP substrate [16, 18, 19]. ALS-induced P-gp upregulation could further restrict riluzole permeability across CNS barriers and reduce its concentration at neuronal target sites, thereby lowering its therapeutic efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…Riluzole is the only FDA-approved ALS drug in the clinic, yet it only modestly slows ALS progression during early disease stages in some patients and does not halt or reverse ALS [6]. Since riluzole is a substrate for two ABC xenobiotic efflux transporters, P-gp and BCRP, the full therapeutic efficacy of riluzole in the CNS could be limited by these efflux transporters at the BBB and BSCB [16, 18, 19]. Recent in vivo studies using mouse models of ALS showed that P-gp and BCRP transport activity and expression were induced in CNS barriers during the late stage of disease progression [15, 17].…”

Section: Introductionmentioning

confidence: 99%

Selective induction of P-glycoprotein at the CNS barriers during symptomatic stage of an ALS animal model

Chan

Evans

Banks

et al. 2017

Neuroscience Letters

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P-glycoprotein (P-gp), Breast cancer resistance protein (BCRP) and Multidrug resistance-associated protein 2 (MRP2) residing at the blood-brain barrier (BBB) and the blood-spinal cord barrier (BSCB) are major obstacles for drug delivery to the Central Nervous System (CNS). Disease-induced changes of these xenobiotic transporters at the CNS barriers have been previously documented. Changes in the functional expression of these transporters at the CNS barriers would limit the clinical efficacy of therapeutic agents targeting the CNS. In this study, we characterized the changes in expression and efflux activity of P-gp, BCRP and MRP2 at the BBB and BSCB of an amyotrophic lateral sclerosis (ALS) SOD1-G93A transgenic rat model across the three stages of disease progression: pre-onset, onset and symptomatic. Up-regulation of P-gp and BCRP at the BBB and BSCB during disease progression of ALS would reduce drug entry to the CNS, while any decreases in transport activity would increase drug entry. In SOD rats at the ALS symptomatic stage, we observed increases in both P-gp transport activity and expression compared to age-matched wildtypes. BCRP and MRP2 levels were unchanged in these animals. Immunohistochemical analysis in brain and spinal cord capillaries of SOD rats from all three ALS stages and age-matched wildtypes showed no differences in nuclear localization of a known P-gp regulator, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). It suggests that NFκB may have a limited role during P-gp induction observed in our study and additional signaling pathways could be responsible for this response. Our observations imply that novel pharmacological approaches for treating ALS require selecting drugs that are not P-gp substrates in order to improve therapeutic efficacy in the CNS during ALS progression.

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Inhibiting drug efflux transporters improves efficacy of ALS therapeutics

Cited by 83 publications

References 37 publications

CNS uptake of bortezomib is enhanced by P-glycoprotein inhibition: implications for spinal muscular atrophy

CNS uptake of bortezomib is enhanced by P-glycoprotein inhibition: implications for spinal muscular atrophy

Astrocytes drive upregulation of the multidrug resistance transporter ABCB1 (P‐Glycoprotein) in endothelial cells of the blood–brain barrier in mutant superoxide dismutase 1‐linked amyotrophic lateral sclerosis

Selective induction of P-glycoprotein at the CNS barriers during symptomatic stage of an ALS animal model

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