ABCG2: Recent Discovery of Potent and Highly Selective Inhibitors

Lecerf-Schmidt, Florine; Pérès, Basile; Valdameri, Gláucio; Gauthier, Charlotte; Winter, Evelyn; Payen, Léa; Pietro, Attilio Di; Boumendjel, Ahcène

doi:10.4155/fmc.13.71

Cited by 26 publications

(31 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These three transporters have an extensive overlap in drug specificity offering tumor resistance to the principal classes of chemotherapeutic drugs and molecularly targeted therapies [32,33,173]. Inhibition of ABCG2 transporter activity with phosphodiesterase-5 inhibitors and fumitremorgin-type indolyldiketopiperazine, Ko143, might intensify the efficacy of the chemotherapeutic agents [174,175]. In addition, Martin and colleagues documented that melatonin increases the efficacy of chemotherapeutic agents, targeting both the tumor bulk and brain tumor stem cells (BTSCs) through the regulation of the expression and function of the ABCG2/BCRP transporter by inducing the methylation of its promoter [18].…”

Section: Discussionmentioning

confidence: 99%

The impact of melatonin and carbon ion irradiation on cancer stem cells

Liu¹,

Reíter²

2017

Nucl Med Biomed Imaging

View full text Add to dashboard Cite

Aim: Cancer stem cells (CSCs) exhibited an excessive migratory and invasive potential. Melatonin may inhibit multiple crucial signals associated with tumor stem cell self-renewal, viability, invasiveness, tumor growth, and therapy resistance. Carbon ion irradiation may be a promising therapeutic modality in both non-stem-like and stem-like tumor cells in contrast to photon irradiation. A comprehensive understanding of the mechanisms and molecular pathways associated with invasive properties of CSCs is essential in developing novel treatment options for cancer therapy that target CSCs. Materials and methods:A systematic review of the existing literature was conducted using the following search terms: 'melatonin', 'X-ray irradiation', 'charged particle irradiation', 'carbon ion irradiation', 'cancer stem cells', 'tumor-initiating cells' and 'cancer stem-like cells'. The search used PubMed and spanned the period from January 2000 to December 2016. Conclusion:Cancer stem cells possess the capacity of self-renewal and pluripotency, generating all cells within a tumor, and are responsible for tumor growth, therapy resistance and metastasis. Melatonin attenuated AKT activation, EZH2 S21 phosphorylation, EZH2-STAT3 interactions and altered histone modifications to reduce tumor initiation and propagation of brain tumor stem cells (BTSC). Melatonin increases the efficacy of chemotherapeutic agents, targeting both the tumor bulk and BTSCs through the regulation of the expression and function of the ABCG2/BCRP transporter by inducing the methylation of its promoter. Melatonin treatment induced cell death with ultrastructural characteristics of autophagy. Breast cancer stem cells (BCSCs) are responsive to melatonin treatment by way of reducing the viability and the invasiveness of breast cancer mammospheres as well as regulating the expression of OCT4, N-cadherin and vimentin proteins associated with epithelial mesenchymal transition in BCSCs. Carbon irradiation is effective in brain tumor stem cell (BTSC) elimination with relative biologic effectiveness (RBE) in the range of 1.87-3.44. Carbon ion irradiation may be a promising therapeutic modality because it reduces migration and invasion processes in both head and neck squamous cell carcinoma and cancer stem cells in contrast to photon irradiation. Low LET X-ray irradiation may essentially eradicate the non-stem-like tumor cells, consequently the radioresistant cancer stem-like cell population is obviously enriched. In contrast, carbon ion irradiation may eradicate both non-stemlike and stem-like tumor cells at the same time. Carbon ion irradiation is a promising tool to eradicate putative colon cancer stem-like cells. Further investigation to elucidate the mechanisms and molecular pathways involved in cancer stem cells particularly associated with melatonin and carbon ion irradiation certainly is warranted.

show abstract

Section: Discussionmentioning

confidence: 99%

The impact of melatonin and carbon ion irradiation on cancer stem cells

Liu¹,

Reíter²

2017

Nucl Med Biomed Imaging

View full text Add to dashboard Cite

show abstract

“…Previous studies showed, in tumor cell lines, that ABCG2 conferred resistance to various chemotherapeutic drugs, including topotecan (36). However, established tumor cell lines do not always recapitulate ABC transporter expression and function in vivo (37).…”

Section: Discussionmentioning

confidence: 99%

ABCG2 Transporter Expression Impacts Group 3 Medulloblastoma Response to Chemotherapy

et al. 2015

View full text Add to dashboard Cite

While a small number of plasma membrane ABC transporters can export chemotherapeutic drugs and confer drug resistance, it is unknown if these transporters are expressed or functional in less therapeutically tractable cancers such as Group3 medulloblastoma (G3 MB). Herein we show that among this class of drug transporters only ABCG2 was expressed at highly increased levels in human G3 MB and a mouse model of this disease. In the mouse model, Abcg2 protein was expressed at the plasma membrane where it functioned as expected based on export of prototypical substrates. By screening ABC substrates against mouse G3 MB tumorspheres in vitro, we found that Abcg2 inhibition could potentiate responses to the clinically employed drug topotecan, producing a >9-fold suppression cell proliferation. Extended studies in vivo in this model confirmed that Abcg2 inhibition was sufficient to enhance antiproliferative responses to topotecan, producing a significant survival advantage compared to subjects treated with topotecan alone. Our findings offer a preclinical proof of concept for blockade of ABCG2 transporter activity as a strategy to empower chemotherapeutic responses in Group3 medulloblastoma.

show abstract

“…They also play a critical role in the induction of multidrug resistance (MDR) in tumor cells [5]. Significant drug discovery efforts have been aimed at developing inhibitors for ABC transporters [6,7], but little is still known about their substrate preference. While recent structural advances have helped close knowledge gaps about the substrate polyspecificity of ABCB1/Abcb1 [8], the lack of detailed structural information about ABCG2/Abcg2 renders the pharmacophore characterization of its substrates more problematic.…”

Section: Introductionmentioning

confidence: 99%

Structural determinants of peripheral O-arylcarbamate FAAH inhibitors render them dual substrates for Abcb1 and Abcg2 and restrict their access to the brain

Moreno-Sanz

Barrera

Armirotti

et al. 2014

Pharmacological Research

View full text Add to dashboard Cite

The blood-brain barrier (BBB) is the main entry route for chemicals into the mammalian central nervous system (CNS). Two transmembrane transporters of the ATP-binding cassette (ABC) family – Breast Cancer Resistance Protein (ABCG2 in humans, Abcg2 in rodents) and P-glycoprotein (ABCB1 in humans, Abcb1 in rodents) – play a key role in mediating this process. Pharmacological and genetic evidence suggests that Abcg2 prevents CNS access to a group of highly potent and selective O-arylcarbamate fatty-acid amidohydrolase (FAAH) inhibitors, which include the compound URB937 (cyclohexylcarbamic acid 3′-carbamoyl-6-hydroxybiphenyl-3-yl ester). To define structure-activity relationships of the interaction of these molecules with Abcg2, in the present study we tested various peripherally restricted and non-restricted O-arylcarbamate FAAH inhibitors for their ability to serve as transport substrates in monolayer cultures of Madin-Darby Canine Kidney-II (MDCKII) cells over-expressing Abcg2. Surprisingly, we found that the majority of compounds tested – even those able to enter the CNS in vivo – were substrates for Abcg2 in vitro. Additional experiments in MDCKII cells overexpressing ABCB1 revealed that only those compounds that were dual substrates for ABCB1 and Abcg2 in vitro were also peripherally restricted in vivo. The extent of such restriction seems to depend upon other physicochemical features of the compounds, in particular the polar surface area. Consistent with these in vitro results, we found that URB937 readily enters the brain in dual knockout mice lacking both Abcg2 and Abcb1, whereas it is either partially or completely excluded from the brain of mice lacking either transporter alone. The results suggest that Abcg2 and Abcb1 act together to restrict the access of URB937 to the CNS.

show abstract

ABCG2: Recent Discovery of Potent and Highly Selective Inhibitors

Cited by 26 publications

References 48 publications

The impact of melatonin and carbon ion irradiation on cancer stem cells

The impact of melatonin and carbon ion irradiation on cancer stem cells

ABCG2 Transporter Expression Impacts Group 3 Medulloblastoma Response to Chemotherapy

Structural determinants of peripheral O-arylcarbamate FAAH inhibitors render them dual substrates for Abcb1 and Abcg2 and restrict their access to the brain

Contact Info

Product

Resources

About