BMS-599626, a highly selective pan-her kinase inhibitor, antagonizes ABCG2-mediated drug resistance

Ashar，Yunali V.1; Zhou，Jingchun2; Gupta，Pranav1; Teng，Qiu Xu1; Lei，Zi Ning1; Reznik，Sandra E.1,3; Lusvarghi，Sabrina4; Wurpel，John1; Ambudkar，Suresh V.4; Chen，Zhe Sheng1

2020-09-01

10.3390/cancers12092502

Cancers   影响因子和分区

2072-6694

2072-6694

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.

ABC transporters ABCG2 BMS-599626 Chemotherapy HER kinase inhibitor Multidrug resistance

SCI

英语

其他

Oncology

Oncology

WOS:000581259400001

MDPI

2-s2.0-85090387085

Scopus

1.Department of Pharmaceutical Sciences,College of Pharmacy and Health Sciences,St. John’s University,Queens,11439,United States
2.Department of Otorhinolaryngology,Shenzhen People’s Hospital (The Second Medical College,Jinan University,The First Affiliated Hospital,Southern University of Science and Technology),Shenzhen,518020,China
3.Departments of Pathology and Obstetrics and Gynecology and Women’s Health,Albert Einstein College of Medicine,Bronx,10461,United States
4.Laboratory of Cell Biology,Center for Cancer Research,National Cancer Institute,NIH,Bethesda,20892,United States

Ashar，Yunali V.,Zhou，Jingchun,Gupta，Pranav,et al. BMS-599626, a highly selective pan-her kinase inhibitor, antagonizes ABCG2-mediated drug resistance[J]. Cancers,2020,12(9):1-15.

Ashar，Yunali V..,Zhou，Jingchun.,Gupta，Pranav.,Teng，Qiu Xu.,Lei，Zi Ning.,...&Chen，Zhe Sheng.(2020).BMS-599626, a highly selective pan-her kinase inhibitor, antagonizes ABCG2-mediated drug resistance.Cancers,12(9),1-15.

Ashar，Yunali V.,et al."BMS-599626, a highly selective pan-her kinase inhibitor, antagonizes ABCG2-mediated drug resistance".Cancers 12.9(2020):1-15.