Sitravatinib, a Tyrosine Kinase Inhibitor, Inhibits the Transport Function of ABCG2 and Restores Sensitivity to Chemotherapy-Resistant Cancer Cells in vitro

Yang, Yuqi; Ji, Ning; Teng, Quincy; Cai, Chao-Yun; Wang, Jingquan; Wu, Zhuo‐Xun; Lei, Zi‐Ning; Lusvarghi, Sabrina; Ambudkar, Suresh V.; Chen, Zhe‐Sheng

doi:10.3389/fonc.2020.00700

Cited by 26 publications

(20 citation statements)

References 46 publications

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“…The vanadate-sensitive ATPase activity of ABCG2 was measured, as previously described, based on the amount of inorganic phosphate (P i ) produced from hydrolyzed ATP ( Yang et al, 2020 ). The amount of P i was quantified by a modified colorimetric method of Murphy and Riley ( Ojida et al, 2004 ).…”

Section: Methodsmentioning

confidence: 99%

OTS964, a TOPK Inhibitor, Is Susceptible to ABCG2-Mediated Drug Resistance

Yang

Wang

et al. 2021

Front. Pharmacol.

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OTS964 is a potent T-LAK cell-originated protein kinase (TOPK) inhibitor. Herein, we investigated the interaction of OTS964 and multidrug resistance (MDR)-associated ATP-binding cassette sub-family G member 2 (ABCG2). The cell viability assay indicated that the effect of OTS964 is limited in cancer drug-resistant and transfected cells overexpressing ABCG2. We found that the known ABCG2 transporter inhibitor has the ability to sensitize ABCG2-overexpressing cells to OTS964. In mechanism-based studies, OTS964 shows inhibitory effect on the efflux function mediated by ABCG2, and in turn, affects the pharmacokinetic profile of other ABCG2 substrate-drugs. Furthermore, OTS964 upregulates ABCG2 protein expression, resulting in enhanced resistance to ABCG2 substrate-drugs. The ATPase assay demonstrated that OTS964 stimulates ATPase activity of ABCG2 in a concentration-dependent manner. The computational molecular docking analysis combined with results from ATPase assay suggested that OTS964 interacts with drug-binding pocket of ABCG2 and has substrate-like behaviors. Thus, OTS964 is an MDR-susceptible agent due to its interactions with ABCG2, and overexpression of ABCG2 transporter may attenuate its therapeutic effect in cancer cells.

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Section: Methodsmentioning

confidence: 99%

OTS964, a TOPK Inhibitor, Is Susceptible to ABCG2-Mediated Drug Resistance

Yang

Wang

et al. 2021

Front. Pharmacol.

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“…The log scale curves in GraphPad (log inhibitor vs. responses) were used to fit cell viability curves and to calculate the IC 50 values. The values of resistance fold (RF) were calculated as previously stated ( 19 ).…”

Section: Methodsmentioning

confidence: 99%

“…As previously described, the protein expression level of ABCC1 was examined by a Western blot analysis ( 19 ). In short, cells were treated with or without betulin, and then the lysate was collected.…”

Section: Methodsmentioning

confidence: 99%

Overexpression of ABCC1 Confers Drug Resistance to Betulin

et al. 2021

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Betulin is a lupane-type pentacyclic triterpene, which is isolated from birch bark. It has a broad spectrum of biological and pharmacological properties, such as anti-inflammatory, anti-tumor, anti-viral, and anti-bacterial activity. Herein, we explored the factors that may result in betulin resistance, especially with respect to its interaction with ATP-binding cassette subfamily C member 1 (ABCC1). ABCC1 is an important member of the ATP-binding cassette (ABC) transporter family, which is central to mediating multidrug resistance (MDR) in naturally derived anticancer agents. An MTT-based cell viability assay showed that ABCC1 overexpression has the ability to desensitize both cancer cell line and gene-transfected cell line to betulin and that this betulin-induced resistance can be antagonized by a known ABCC1 inhibitor MK571 at 25 μM. Additionally, betulin upregulates the ABCC1 protein expression level in both concentration-dependent and time-dependent manners, also blocks the transport function mediated by ABCC1. Subsequently, a high affinity score of betulin was achieved in a computational docking analysis, demonstrating a strong interaction of betulin with ABCC1.

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“…The top-scored AZ-628 docked into ABCG2 model was used for MD simulation as previously described ( Yang et al, 2020b ). In brief, AZ-628-ABCG2 complex model was loaded into Desmond developed by DE Shaw Research Group.…”

Section: Methodsmentioning

confidence: 99%

Reversal of Cancer Multidrug Resistance (MDR) Mediated by ATP-Binding Cassette Transporter G2 (ABCG2) by AZ-628, a RAF Kinase Inhibitor

Wang

Teng

Lei

et al. 2020

Front. Cell Dev. Biol.

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Overexpression of ABCG2 remains a major impediment to successful cancer treatment, because ABCG2 functions as an efflux pump of chemotherapeutic agents and causes clinical multidrug resistance (MDR). Therefore, it is important to uncover effective modulators to circumvent ABCG2-mediated MDR in cancers. In this study, we reported that AZ-628, a RAF kinase inhibitor, effectively antagonizes ABCG2-mediated MDR in vitro. Our results showed that AZ-628 completely reversed ABCG2-mediated MDR at a non-toxic concentration (3 μM) without affecting ABCB1-, ABCC1-, or ABCC10 mediated MDR. Further studies revealed that the reversal mechanism was by attenuating ABCG2-mediated efflux and increasing intracellular accumulation of ABCG2 substrate drugs. Moreover, AZ-628 stimulated ABCG2-associated ATPase activity in a concentration-dependent manner. Docking and molecular dynamics simulation analysis showed that AZ-628 binds to the same site as ABCG2 substrate drugs with higher score. Taken together, our studies indicate that AZ-628 could be used in combination chemotherapy against ABCG2-mediated MDR in cancers.

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Sitravatinib, a Tyrosine Kinase Inhibitor, Inhibits the Transport Function of ABCG2 and Restores Sensitivity to Chemotherapy-Resistant Cancer Cells in vitro

Cited by 26 publications

References 46 publications

OTS964, a TOPK Inhibitor, Is Susceptible to ABCG2-Mediated Drug Resistance

OTS964, a TOPK Inhibitor, Is Susceptible to ABCG2-Mediated Drug Resistance

Overexpression of ABCC1 Confers Drug Resistance to Betulin

Reversal of Cancer Multidrug Resistance (MDR) Mediated by ATP-Binding Cassette Transporter G2 (ABCG2) by AZ-628, a RAF Kinase Inhibitor

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