ABCG2-overexpressing H460/MX20 cell xenografts in athymic nude mice maintained original biochemical and cytological characteristics

Zhang, Wei; Chen, Zhen; Chen, Likun; Wang, Fang; Li, Furong; Wang, Xiaokun; Fu, Liwu

doi:10.1038/srep40064

Cited by 8 publications

(8 citation statements)

References 30 publications

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“…29 Through dividing the IC 50 of cells free from CM082 with the IC 50 of cells in the presence of CM082, we obtained the fold reversal of MDR. 30 All assays were performed in triplicate, and mean ± standard deviation (SD) was used to describe the related data.…”

Section: Cell Cytotoxicity Assaymentioning

confidence: 99%

CM082 Enhances the Efficacy of Chemotherapeutic Drugs by Inhibiting the Drug Efflux Function of ABCG2

Huang

et al. 2020

Molecular Therapy - Oncolytics

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Section: Cell Cytotoxicity Assaymentioning

confidence: 99%

CM082 Enhances the Efficacy of Chemotherapeutic Drugs by Inhibiting the Drug Efflux Function of ABCG2

Huang

et al. 2020

Molecular Therapy - Oncolytics

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“…The H460/MX20 cell xenograft model was established as previously described with minor modifications [ 27 ]. Athymic nude mice (BALB/c-nu/nu, female, 5 to 6 weeks old, 17~22 g) were provided by the Vital River (Beijing, China).…”

Section: Methodsmentioning

confidence: 99%

Dacomitinib potentiates the efficacy of conventional chemotherapeutic agents via inhibiting the drug efflux function of ABCG2 in vitro and in vivo

Guo¹,

To²,

Chen³

et al. 2018

J Exp Clin Cancer Res

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BackgroundATP-binding cassette subfamily G member 2 (ABCG2), a member of the ABC transporter superfamily proteins, mediates multidrug resistance (MDR) by transporting substrate anticancer drugs out of cancer cells and decreasing their intracellular accumulation. MDR is a major hurdle to successful chemotherapy. A logical approach to overcome MDR is to inhibit the transporter. However, no safe and effective MDR inhibitor has been approved in the clinic.MethodsThe MTT assay was used to evaluate cell cytotoxicity and MDR reversal effect. Drug efflux and intracellular drug accumulation were measured by flow cytometry. The H460/MX20 cell xenograft model was established to evaluate the enhancement of anticancer efficacy of topotecan by dacomitinib in vivo. To ascertain the interaction of dacomitinib with the substrate binding sites of ABCG2, the competition of dacomitinib for photolabeling of ABCG2 with [125I]- iodoarylazidoprazosin (IAAP) was performed. Vanadate-sensitive ATPase activity of ABCG2 was measured in the presence of a range of different concentrations of dacomitinib to evaluate the effect of dacomitinib on ATP hydrolysis as the energy source of the transporter. A flow cytometry-based assay and western blotting were employed to study whether dacomitininb could inhibit the expression level of ABCG2. The mRNA expression levels of ABCG2 were analyzed by real-time quantitative RT-PCR. The protein expression level of AKT, ERK and their phosphorylations were detected by Western blotting.ResultsHere, we found that dacomitinib, an irreversible pan-ErbB tyrosine kinase inhibitor (TKI) in phase III clinical trial, could enhance the efficacy of conventional chemotherapeutic agents specifically in ABCG2-overexpressing MDR cancer cells but not in the parental sensitive cells. Dacomitinib was found to significantly increase the accumulation of ABCG2 probe substrates [doxorubicin (DOX),Rhodamine 123 (Rho 123) and Hoechst 33342] by inhibiting the transporter efflux function. Moreover, dacomitinib stimulated ABCG2 ATPase activity and competed with [125I]-IAAP photolabeling of ABCG2 in a concentration-dependent manner. However, dacomitinib did not alter ABCG2 expression at protein and mRNA levels or inhibit ErbB downstream signaling of AKT and ERK. Importantly, dacomitinib significantly enhanced the efficacy of topotecan in ABCG2-overexpressing H460/MX20 cell xenografts in nude mice without incurring additional toxicity.ConclusionsThese results suggest that dacomitinib reverses ABCG2-mediated MDR by inhibiting ABCG2 efflux function and increasing intracellular accumulation of anticancer agents. Our findings advocate further clinical investigation of combinations of dacomitinib and conventional chemotherapy in cancer patients with ABCG2-overexpressing MDR tumors.

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“…Because the functions of ABC transporters are involved in the clinical multi drug resistance, combination therapies of ABC transporter inhibitors and some anti-cancer drugs have been tested. The inhibitor of ABCG2 induced the drug efficacy of mitoxantrone and topotecan to lung cancer cells which overexpress ABC transporters [83] . Rabindran et al [84] checked that Fumitremorgin C reversed the sensitivities to mitoxantrone, doxorubicin, and topotecan through inhibiting the function of ABCG2.…”

Section: Overexpression Of Atp-binding Cassette (Transporter Proteinsmentioning

confidence: 99%

Drug resistance mechanisms of cancer stem-like cells and their therapeutic potential as drug targets

Murayama¹,

Gotoh²

2019

CDR

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Despite of recent advances in cancer research and development of new anti-cancer drugs, tumor patients' prognoses have not yet been improved well enough. Treatment failure of tumors is highly attributed to the drug resistance of a small population of cancer cell known as cancer stem-like cells (CSCs). CSCs also have the self-renewal activity and differentiation potency, conferring strong tumorigenicity on them. Therefore, development of CSC targeting therapy is urgently needed in order to overcome possible recurrence and metastasis by them after therapy. CSCs show some characteristic features that are not observed in other differentiated cancer cells, which give them higher resistance against conventional chemotherapy or radiotherapy. Targeting such specific features could be useful for CSC eradication. This review will summarize the recent advances in the study of CSC characteristics along with the promising therapeutic strategies targeting them.

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ABCG2-overexpressing H460/MX20 cell xenografts in athymic nude mice maintained original biochemical and cytological characteristics

Cited by 8 publications

References 30 publications

CM082 Enhances the Efficacy of Chemotherapeutic Drugs by Inhibiting the Drug Efflux Function of ABCG2

CM082 Enhances the Efficacy of Chemotherapeutic Drugs by Inhibiting the Drug Efflux Function of ABCG2

Dacomitinib potentiates the efficacy of conventional chemotherapeutic agents via inhibiting the drug efflux function of ABCG2 in vitro and in vivo

Drug resistance mechanisms of cancer stem-like cells and their therapeutic potential as drug targets

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