Distribution of STI-571 to the Brain Is Limited by P-Glycoprotein-Mediated Efflux

Dai, Hai Qing; Marbach, Peter; Lemaire, Michel; Hayes, M.; Elmquist, William F.

doi:10.1124/jpet.102.045260

Cited by 239 publications

(200 citation statements)

References 37 publications

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“…To determine whether an inhibitor of c-Abl protects against the MPTP-induced loss of dopaminergic neurons, we treated animals with STI571, a c-Abl family kinase inhibitor, before or after exposure to MPTP (Figure 2a). It has been shown that intraperitoneally injected STI571 could penetrate into brain, 15 and we confirmed the presence of STI571 in the ventral midbrain by intraperitoneal injection in our experiments (Figure 2b). Moreover, we found that intraperitoneal injection of STI571 did not affect the concentration of MPP + , the metabolite of MPTP, in the striatum (Figure 2c).…”

Section: Resultssupporting

confidence: 88%

c-Abl–p38α signaling plays an important role in MPTP-induced neuronal death

Chen

et al. 2015

Cell Death Differ

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Oxidative stress is a major cause of sporadic Parkinson's disease (PD). Here, we demonstrated that c-Abl plays an important role in oxidative stress-induced neuronal cell death. C-Abl, a nonreceptor tyrosine kinase, was activated in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced acute PD model. Conditional knockout of c-Abl in neurons or treatment of mice with STI571, a c-Abl family kinase inhibitor, reduced the loss of dopaminergic neurons and ameliorated the locomotive defects induced by short-term MPTP treatment. By combining the SILAC (stable isotope labeling with amino acids in cell culture) technique with other biochemical methods, we identified p38α as a major substrate of c-Abl both in vitro and in vivo and c-Ablmediated phosphorylation is critical for the dimerization of p38α. Furthermore, p38α inhibition mitigated the MPTP-induced loss of dopaminergic neurons. Taken together, these data suggested that c-Abl-p38α signaling may represent a therapeutic target for PD. Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by bradykinesia, rigidity, tremor, and loss of dopaminergic neurons. 1 Familial mutations that cause PD have been identified, including in the genes that encode α-synuclein and leucine-rich repeat kinase 2 (LRRK2) that cause autosomal-dominant PD, and DJ-1, PINK1, and parkin that cause autosomal-recessive PD. 2 However, the majority of PD cases are sporadic. The cause of sporadic PD remains unknown, and the role of environmental toxins and genetic factors in sporadic PD is unclear. However, the evidence regarding postencephalitic PD and the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced Parkinsonism suggest that environmental toxins may be a major cause of sporadic PD. 3,4 The neurotoxins used to induce dopaminergic neurodegeneration, including 6-hydroxydopamine, MPTP, and rotenone, induce the formation of reactive oxygen species (ROS). ROS react with nucleic acids, proteins, and lipids to induce mitochondrial damage. Although oxidative stress plays a critical role in causing PD, the mechanisms underlying oxidative stress-induced PD remain unclear.The nonreceptor tyrosine kinase c-Abl is ubiquitously expressed and mediates a variety of extrinsic and intrinsic cell signaling activities, including growth factor signaling, cell adhesion, oxidative stress, and DNA damage. 5 Our group and other groups have reported that c-Abl plays an important role in oxidative stress-induced neuronal death. 6-8 Recently, Ko et al. 9 and Imam et al. 10 have reported that c-Abl phosphorylated Parkin and inhibited its E3 ligase activity that led to the neurotoxic accumulation of Parkin's substrates. α-Synuclein has also been reported to be substrates of c-Abl and to participate in PD pathogenesis. 9-11 The c-Abl inhibitor Nilotinib and INNO-406 have been reported prevents the loss of dopamine neurons and improves motor behavior in a murine PD model. [12][13][14] In this study, we demonstrated that c-Abl ...

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Section: Resultssupporting

confidence: 88%

c-Abl–p38α signaling plays an important role in MPTP-induced neuronal death

Chen

et al. 2015

Cell Death Differ

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“…It has been reported that IM inhibits the growth of glioma cells in preclinical models, but has poor distribution in the nervous system due to the fact that p-Gp limits its efficacy in patients (14). The results of this study show that CAR provides a synergistic effect on IM-induced cytotoxicity in monolayer and spheroid cultures of malignant C6 glioma cells.…”

Section: Discussionsupporting

confidence: 56%

“…IM has recently been shown to be efficacious in preclinical studies for GBM. Unfortunately, the potential utility of IM has been hampered by problems with drug distribution to the nervous system, as IM is a substrate of P-glycoprotein (p-Gp; the product of MDR1 gene), an active efflux transporter, thus limiting the distribution of IM to the central nervous system (14). Fortunately, the use of p-Gp inhibitors to improve brain penetration of p-Gp substrate drugs has been shown to be effective in both animal and human studies (15).…”

Section: Introductionmentioning

confidence: 99%

Carvedilol in glioma treatment alone and with imatinib in vitro

Ergüven

Yazıhan

Aktaş³

et al. 2010

Int J Oncol

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Abstract. The purpose of the study was to investigate whether carvedilol has an antiproliferative effect alone and whether carvedilol provides an additive, synergistic or antagonistic effect on imatinib mesylate-induced cytotoxicity in both C6 glioma monolayer and spheroid culture. The C6 rat glioma chemoresistant experimental brain tumour cell line, that is notoriously difficult to treat with combination chemotherapy, was used both in monolayer and spheroid cultures. We treated C6 glioma cells with carvedilol alone and a combination of carvedilol and imatinib mesylate at a concentration of 10 μM. Following treatment, we evaluated cell proliferation index, bromodeoxyuridine labelling index (BrDU-LI), cell cycle distributions, apoptotic cell percentages, cAMP levels and three dimensional cell morphology at monolayer cultures. In addition BrDU-LI, volume and morphology of spheroids were also assessed. Carvedilol and imatinib mesylate alone reduced cell number, BrDU-LI, cAMP levels and spheroid volume. Carvedilol and imatinib mesylate arrested cells at G0/ G1 phase in a time-dependent manner and time-independent manner, respectively. Carvedilol increased apoptosis rate only at the 24th h, but imatinib mesylate did for all time intervals. Interestingly carvedilol, drug with well-known protective effect on mitochondria, induced severe mitochondria damage, and imatinib mesylate induced autophagy confirmed only by transmission electron microscopy. These results suggest that carvedilol showed antitumour activity against rat C6 glioma cells and a combination of carvedilol with imatinib mesylate resulted in enhanced in vitro antitumour activity.

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“…Several studies have confirmed that imatinib interacts with the multidrug transporter proteins, MDR1 (multidrug resistance protein 1, also known as P-glycoprotein) [38][39][40] and MXR (multixenobiotic resistance protein, also known as breast-cancer resistance protein). [41][42][43] Increased expression of these two efflux proteins reduces intracellular concentrations of imatinib and decreases the antiproliferative effects of the drug.…”

Section: Intracellular Imatinib Concentrationsmentioning

confidence: 99%