Obstacles to Brain Tumor Therapy: Key ABC Transporters

Wijaya, Juwina; Fukuda, Yu; Schuetz, John D.

doi:10.3390/ijms18122544

Cited by 73 publications

(42 citation statements)

References 152 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As a corollary to these reports, our data indicate that attenuation of TMZinduced G2/M arrest by ABCB5 blockade sensitized GBM cells to drug-mediated death as was evident from increased apoptosis, and decreased proliferation of GBM cells upon combined treatment with TMZ and ABCB5 mAb. Nevertheless, we cannot exclude that, in addition to cell cycle regulation, ABCB5 might also function as a GBM efflux transporter, a function previously attributed to other ABC family members such as ABCB1 and ABCG2 (45)(46)(47). Further studies would be required to investigate this possibility.…”

Section: Discussionmentioning

confidence: 93%

Targeting the ABC transporter ABCB5 sensitizes glioblastoma to temozolomide-induced apoptosis through a cell-cycle checkpoint regulation mechanism

Lee

Banerjee

Wilson

et al. 2020

Journal of Biological Chemistry

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) is a malignant brain tumor with a poor prognosis resulting from tumor resistance to anticancer therapy and a high recurrence rate. Compelling evidence suggests that this is driven by subpopulations of cancer stem cells (CSCs) with tumor-initiating potential. ABC subfamily B member 5 (ABCB5) has been identified as a molecular marker for distinct subsets of chemoresistant tumor-initiating cell populations in diverse human malignancies. In the current study, we examined the potential role of ABCB5 in growth and chemoresistance of GBM. We found that ABCB5 is expressed in primary GBM tumors, in which its expression was significantly correlated with the CSC marker protein CD133 and with overall poor survival. Moreover, ABCB5 was also expressed by CD133-positive CSCs in the established human U-87 MG, LN-18, and LN-229 GBM cell lines. Antibody- or shRNA-mediated functional ABCB5 blockade inhibited proliferation and survival of GBM cells and sensitized them to temozolomide (TMZ)-induced apoptosis in vitro. Likewise, in in vivo human GBM xenograft experiments with immunodeficient mice, mAb treatment inhibited growth of mutant TP53, WT PTEN LN-229 tumors, and sensitized LN-229 tumors to TMZ therapy. Mechanistically, we demonstrate that ABCB5 blockade inhibits TMZ-induced G2/M arrest and augments TMZ-mediated cell death. Our results identify ABCB5 as a GBM chemoresistance marker and point to the potential utility of targeting ABCB5 to improve current GBM therapies.

show abstract

Section: Discussionmentioning

confidence: 93%

Targeting the ABC transporter ABCB5 sensitizes glioblastoma to temozolomide-induced apoptosis through a cell-cycle checkpoint regulation mechanism

Lee

Banerjee

Wilson

et al. 2020

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Of the transporters included in the FDA guidance Abcb1a and Abcg2 were found to be expressed at high and similar levels across the brain, liver, and kidneys (FDA, 2017). ABCB1 and ABCG2 are among the most highly expressed transporters on the BBB in humans, and this is mirrored in their rat homologues (Wijaya et al , 2017).…”

Section: Discussionmentioning

confidence: 99%

Temporal Profile of Transporter mRNA Expression in the Brain after Traumatic Brain Injury in Developing Rats

Cheng

et al. 2019

Preprint

View full text Add to dashboard Cite

Traumatic brain injury (TBI) is a leading cause of death in children and young adults; however, new pharmacologic approaches have failed to improve outcomes in clinical trials. Transporter proteins are central to the maintenance of homeostasis within the neurovascular unit, and regulate drug penetration into the brain. Our objective was to measure transporter temporal changes in expression in the hippocampus and cortex after experimental TBI in developing rats. We also evaluated the expression of transporters in brain, liver, and kidney across the age spectrum in both pediatric and adult rats. Eighty post-natal day (PND)-17 rats and four adult rats were randomized to receive controlled cortical impact (CCI), sham surgery, or no surgery. mRNA transcript counts for 27 ATP-binding cassette and solute carrier transporters were measured in the hippocampus, cortex, choroid plexus, liver, and kidney at 3h, 12h, 24h, 72h, 7d, and 14d post injury. After TBI, the expression of many transporters (Abcc2, Slc15a2, Slco1a2) decreased significantly in the first 24 hours, with a return to baseline over 7-14 days. Some transporters (Abcc4, Abab1a/b, Slc22a4) showed a delayed increase in expression. Baseline expression of transporters was of a similar order of magnitude in brain tissues relative to liver and kidney. Findings suggest that transporter-regulated processes may be impaired in the brain early after TBI and are potentially involved in the recovery of the neurovascular unit. Our data also suggest that transport-dependent processes in the brain are of similar importance as those seen in organs involved in drug metabolism and excretion. Significance StatementBaseline transporter mRNA expression in the central nervous system is of similar magnitude as liver and kidney, and experimental traumatic brain injury is associated with acute decrease in expression of several transporters, while others show delayed increase or decrease in expression. Pharmacotherapy following traumatic brain injury should consider potential pharmacokinetic changes associated with transporter expression. Abdel-Razzak Z, Loyer P, Fautrel A, Gautier J, Corcos L, Turlin B, P B, and A. G (1993) Cytokines Expression of Major Cytochrome 450 Enzymes in Adult Human Hepatocytes in Primary Culture. Molecular pharmacology 44:707-15. Adams SM, Conley YP, Ren D, Okonkwo DO, Puccio AM, Dixon CE, Clark RS, Kochanek PM, and Empey PE (2018) ABCG2 c.421C>A Is Associated with Outcomes after Severe Traumatic Brain Injury. Journal of Neurotrauma 35:48-53. Adams SM, Conley YP, Wagner AK, Jha RM, Clark RS, Poloyac SM, Kochanek PM, and Empey PE (2017) The pharmacogenomics of severe traumatic brain injury. Pharmacogenomics pgs-2017-0073. Benjamini Y, and Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. Chuang P-Y, Conley YP, Poloyac SM, Okonkwo DO, Ren D, Sherwood PR, Hravnak M, and Alexander S a (2010) Neuroglobin genetic polymorphisms and their relationship to functional outcomes after traumatic brain injury. Jour...

show abstract

“…conserved "cassette-like" domain that catalyzes the ATP hydrolysis providing the energy needed for the transport of substances against a concentration gradient [39] (Figure 2A). They actively transport both endogenous and exogenous substances and are implicated in the absorption, distribution, and excretion of several xenobiotics [39][40][41][42]. To date, 48 ABC genes and three pseudogenes can be found in humans and, according to the HUGO Gene Nomenclature Committee [43], they are grouped in seven subfamilies named with the letters A-G (i.e., ABCA, ABCB, .…”

Section: The Blood-arachnoid Barriermentioning

confidence: 99%

“…The expression of ABC transporters in cancer cells and the BBB/BBTB has been directly related to chemoresistance against several of their anticancer drug substrates [42,52,53,56,336]. The presence of ABC transporters in both the BBTB and the tumor cancer cells indicate a multibarrier system defending the cancer cells from chemotherapeutics, coupled to detoxifying systems and the anti-apoptotic machinery.…”

Section: Abc Transporters Role In Glioma Drug Resistancementioning

confidence: 99%

“…Study of ABC transporters could lead to personalized medicine strategies. It has been observed that gliomas and its surrounding tissue can present overexpression and even the de novo expression of ABC transporters [14,16,41,42,104], but they are not considered as markers for their subclassification, because there is a high variability in this phenomena, even when the same type and grade of glioma are compared [15,348]. Nevertheless, evaluation of the transporter's expression or activity from biopsy or noninvasive methods (such as PET) could be used to devise personalized strategies for chemotherapies, such as the inhibition of ABC transporters (Section 6) [41].…”

Section: Abc Transporters Role In Glioma Drug Resistancementioning

confidence: 99%

See 1 more Smart Citation

ABC Transporters at the Blood–Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas

et al. 2019

View full text Add to dashboard Cite

Drug delivery into the brain is regulated by the blood–brain interfaces. The blood–brain barrier (BBB), the blood–cerebrospinal fluid barrier (BCSFB), and the blood–arachnoid barrier (BAB) regulate the exchange of substances between the blood and brain parenchyma. These selective barriers present a high impermeability to most substances, with the selective transport of nutrients and transporters preventing the entry and accumulation of possibly toxic molecules, comprising many therapeutic drugs. Transporters of the ATP-binding cassette (ABC) superfamily have an important role in drug delivery, because they extrude a broad molecular diversity of xenobiotics, including several anticancer drugs, preventing their entry into the brain. Gliomas are the most common primary tumors diagnosed in adults, which are often characterized by a poor prognosis, notably in the case of high-grade gliomas. Therapeutic treatments frequently fail due to the difficulty of delivering drugs through the brain barriers, adding to diverse mechanisms developed by the cancer, including the overexpression or expression de novo of ABC transporters in tumoral cells and/or in the endothelial cells forming the blood–brain tumor barrier (BBTB). Many models have been developed to study the phenotype, molecular characteristics, and function of the blood–brain interfaces as well as to evaluate drug permeability into the brain. These include in vitro, in vivo, and in silico models, which together can help us to better understand their implication in drug resistance and to develop new therapeutics or delivery strategies to improve the treatment of pathologies of the central nervous system (CNS). In this review, we present the principal characteristics of the blood–brain interfaces; then, we focus on the ABC transporters present on them and their implication in drug delivery; next, we present some of the most important models used for the study of drug transport; finally, we summarize the implication of ABC transporters in glioma and the BBTB in drug resistance and the strategies to improve the delivery of CNS anticancer drugs.

show abstract

Obstacles to Brain Tumor Therapy: Key ABC Transporters

Cited by 73 publications

References 152 publications

Targeting the ABC transporter ABCB5 sensitizes glioblastoma to temozolomide-induced apoptosis through a cell-cycle checkpoint regulation mechanism

Targeting the ABC transporter ABCB5 sensitizes glioblastoma to temozolomide-induced apoptosis through a cell-cycle checkpoint regulation mechanism

Temporal Profile of Transporter mRNA Expression in the Brain after Traumatic Brain Injury in Developing Rats

ABC Transporters at the Blood–Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas

Contact Info

Product

Resources

About