Dual TTK/CLK2 inhibitor, CC‐671, selectively antagonizes ABCG2‐mediated multidrug resistance in lung cancer cells

Wu, Zhuo‐Xun; Yang, Yuqi; Wang, Guangsuo; Wang, Jingquan; Teng, Quincy; Sun, Lingling; Lei, Zi‐Ning; Lin, Lizhu; Chen, Zhe‐Sheng; Zou, Chang

doi:10.1111/cas.14505

Cited by 30 publications

(30 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Upon treatment with 100 and 300 nM BMS-599626, there was a significant reduction in the IC 50 values of substrate drugs in ABCG2-overexpressing cells, but the IC 50 remained unchanged in the parental NCI-H460 cells. These findings are comparable to Ko143, which is a known inhibitor of ABCG2 [ 26 , 27 ]. There was no change in the IC 50 values of cisplatin upon treatment with 100 and 300 nM BMS-599626 or 300 nM Ko143.…”

Section: Resultssupporting

confidence: 72%

BMS-599626, a Highly Selective Pan-HER Kinase Inhibitor, Antagonizes ABCG2-Mediated Drug Resistance

Ashar

Zhou

Gupta

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

Multidrug resistance (MDR) associated with the overexpression of ABC transporters is one of the key causes of chemotherapy failure. Various compounds blocking the function and/or downregulating the expression of these transporters have been developed over the last few decades. However, their potency and toxicity have always been a concern. In this report, we found that BMS-599626 is a highly potent inhibitor of the ABCG2 transporter, inhibiting its efflux function at 300 nM. Our study repositioned BMS-599626, a highly selective pan-HER kinase inhibitor, as a chemosensitizer in ABCG2-overexpressing cell lines. As shown by the cytotoxicity assay results, BMS-599626, at noncytotoxic concentrations, sensitizes ABCG2-overexpressing cells to topotecan and mitoxantrone, two well-known substrates of ABCG2. The results of our radioactive drug accumulation experiment show that the ABCG2-overexpressing cells, treated with BMS-599626, had an increase in the accumulation of substrate chemotherapeutic drugs, as compared to their parental subline cells. Moreover, BMS-599626 did not change the protein expression or cell surface localization of ABCG2 and inhibited its ATPase activity. Our in-silico docking study also supports the interaction of BMS-599626 with the substrate-binding site of ABCG2. Taken together, these results suggest that administration of chemotherapeutic drugs, along with nanomolar concentrations (300 nM) of BMS-599626, may be effective against ABCG2-mediated MDR in clinical settings.

show abstract

Section: Resultssupporting

confidence: 72%

BMS-599626, a Highly Selective Pan-HER Kinase Inhibitor, Antagonizes ABCG2-Mediated Drug Resistance

Ashar

Zhou

Gupta

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

show abstract

“…Both S1 and S1-IR20 cells were seeded in 24-well plates (1 × 10 6 cells per well). The immunofluorescence experiment was carried out as previously described ( 34 ). The antibodies used in this experiment were anti-ABCG2 (1:1,000, Thermo Fisher Scientific Inc., Waltham, MA) and Alexa Fluor 488 conjugated anti-mouse IgG antibody (1:1,000, Thermo Fisher Scientific Inc., Waltham, MA).…”

Section: Methodsmentioning

confidence: 99%

Establishment and Characterization of an Irinotecan-Resistant Human Colon Cancer Cell Line

Yang

Zeng

et al. 2021

Front. Oncol.

Self Cite

View full text Add to dashboard Cite

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Irinotecan is widely used as a chemotherapeutic drug to treat CRC. However, the mechanisms of acquired resistance to irinotecan in CRC remain inconclusive. In the present study, we established a novel irinotecan-resistant human colon cell line to investigate the underlying mechanism(s) of irinotecan resistance, particularly the overexpression of ABC transporters. The irinotecan-resistant S1-IR20 cell line was established by exposing irinotecan to human S1 colon cancer cells. MTT cytotoxicity assay was carried out to determine the drug resistance profile of S1-IR20 cells. The drug-resistant cells showed about 47-fold resistance to irinotecan and cross-resistance to ABCG2 substrates in comparison with S1 cells. By Western blot analysis, S1-IR20 cells showed significant increase of ABCG2, but not ABCB1 or ABCC1 in protein expression level as compared to that of parental S1 cells. The immunofluorescence assay showed that the overexpressed ABCG2 transporter is localized on the cell membrane of S1-IR20 cells, suggesting an active efflux function of the ABCG2 transporter. This finding was further confirmed by reversal studies that inhibiting efflux function of ABCG2 was able to completely abolish drug resistance to irinotecan as well as other ABCG2 substrates in S1-IR20 cells. In conclusion, our work established an in vitro model of irinotecan resistance in CRC and suggested ABCG2 overexpression as one of the underlying mechanisms of acquired resistance to irinotecan. This novel resistant cell line may enable future studies to overcome drug resistance in vitro and improve CRC treatment in vivo.

show abstract

“…The protein concentration of protein samples was measured by BCA assay kit (Thermo Scientific, Rockford, IL). The immunoblots were performed as previously described ( Wu et al, 2020c ). Briefly, the samples were subjected to SDS-PAGE, then transferred onto PVDF membranes.…”

Section: Methodsmentioning

confidence: 99%

Elevated ABCB1 Expression Confers Acquired Resistance to Aurora Kinase Inhibitor GSK-1070916 in Cancer Cells

Yang

Wang

et al. 2021

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

The emergence of multidrug resistance (MDR) has been a major issue for effective cancer chemotherapy as well as targeted therapy. One prominent factor that causes MDR is the overexpression of ABCB1 transporter. In the present study, we revealed that the Aurora kinase inhibitor GSK-1070916 is a substrate of ABCB1. GSK-1070916 is a newly developed inhibitor that is currently under clinical investigation. The cytotoxicity assay showed that overexpression of ABCB1 significantly hindered the anticancer effect of GSK-1070916 and the drug resistance can be abolished by the addition of an ABCB1 inhibitor. GSK-1070916 concentration-dependently stimulated ABCB1 ATPase activity. The HPLC drug accumulation assay suggested that the ABCB1-overexpressing cells had lower levels of intracellular GSK-1070916 compared with the parental cells. GSK-1070916 also showed high binding affinity to ABCB1 substrate-binding site in the computational docking analysis. In conclusion, our study provides strong evidence that ABCB1 can confer resistance to GSK-1070916, which should be taken into consideration in clinical setting.

show abstract

Dual TTK/CLK2 inhibitor, CC‐671, selectively antagonizes ABCG2‐mediated multidrug resistance in lung cancer cells

Cited by 30 publications

References 54 publications

BMS-599626, a Highly Selective Pan-HER Kinase Inhibitor, Antagonizes ABCG2-Mediated Drug Resistance

BMS-599626, a Highly Selective Pan-HER Kinase Inhibitor, Antagonizes ABCG2-Mediated Drug Resistance

Establishment and Characterization of an Irinotecan-Resistant Human Colon Cancer Cell Line

Elevated ABCB1 Expression Confers Acquired Resistance to Aurora Kinase Inhibitor GSK-1070916 in Cancer Cells

Contact Info

Product

Resources

About