Midostaurin Reverses ABCB1-Mediated Multidrug Resistance, an in vitro Study

Ji, Ning; Yang, Yuqi; Cai, Chao-Yun; Wang, Jing-Quan; Lei, Zi‐Ning; Wu, Zhuo‐Xun; Cui, Qingbin; Yang, Dong‐Hua; Chen, Zhe‐Sheng

doi:10.3389/fonc.2019.00514

Cited by 27 publications

(20 citation statements)

References 48 publications

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“…At present, it is documented that the major mechanism of ABCB1-mediated MDR results from ABCB1 working as a drug efflux pump. Specifically, the chemotherapeutic drugs firstly bind to ABCB1 when crossing the membrane of certain cells, and then the ATP hydrolysis provides energy, which results in pumping the drugs out of the cells; hence, this process could reduce the intracellular concentration of drugs, resulting ABCB1-mediated drug resistance [35][36][37]. Because ABCB1-mediated MDR is one of the key factors leading to the failure of chemotherapy, searching for a promising reversal method to conquer ABCB1 is still urgently needed for solving drug resistance.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of ABCB1 Transporter Confers Resistance to mTOR Inhibitor WYE-354 in Cancer Cells

Wang

Yang

et al. 2020

IJMS

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The overexpressing ABCB1 transporter is one of the key factors leading to multidrug resistance (MDR). Thus, many ABCB1 inhibitors have been found to be able to overcome ABCB1-mediated MDR. However, some inhibitors also work as a substrate of ABCB1, which indicates that in order to achieve an effective reversal dosage, a higher concentration is needed to overcome the pumped function of ABCB1, which may concurrently increase the toxicity. WYE-354 is an effective and specific mTOR (mammalian target of rapamycin) inhibitor, which recently has been reported to reverse ABCB1-mediated MDR. In the current study, 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay was carried out to determine the cell viability and reversal effect of WYE-354 in parental and drug-resistant cells. Drug accumulation was performed to examine the effect of WYE-354 on the cellular accumulation of chemotherapeutic drugs. The ATPase (adenosine triphosphatase) activity of the ABCB1 transporter in the presence or absence of WYE-354 was conducted in order to determine the impact of WYE-354 on ATP hydrolysis. Western blot analysis and immunofluorescence assay were used to investigate the protein molecules related to MDR. In addition, the interaction between the WYE-354 and ABCB1 transporter was investigated via in silico analysis. We demonstrated that WYE-354 is a substrate of ABCB1, that the overexpression of the ABCB1 transporter decreases the efficacy of WYE-354, and that the resistant WYE-354 can be reversed by an ABCB1 inhibitor at a pharmacological achievable concentration. Furthermore, WYE-354 increased the intracellular accumulation of paclitaxel in the ABCB1-mediated MDR cell line, without affecting the corresponding parental cell line, which indicated that WYE-354 could compete with other chemotherapeutic drugs for the ABCB1 transporter substrate binding site. In addition, WYE-354 received a high score in the docking analysis, indicating a strong interaction between WYE-354 and the ABCB1 transporter. The results of the ATPase analysis showed that WYE-354 could stimulate ABCB1 ATPase activity. Treatment with WYE-354 did not affect the protein expression or subcellular localization of the ABCB1. This study provides evidence that WYE-354 is a substrate of the ABCB1 transporter, implicating that WYE-354 should be avoided for use in ABCB1-mediated MDR cancer.

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Section: Discussionmentioning

confidence: 99%

Overexpression of ABCB1 Transporter Confers Resistance to mTOR Inhibitor WYE-354 in Cancer Cells

Wang

Yang

et al. 2020

IJMS

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“…Even though the clinical effect of these ABCG2 inhibitors remains inconclusive, an appropriate modulation of ABCG2 activity may strengthen the efficacy of substrate-drugs by overcoming MDR and improving their pharmacokinetics (41)(42)(43). Recent studies suggest that the combination of several TKIs with substrate-drugs can achieve desired effect and reverse drug resistance (44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells

Peng

Yang

et al. 2020

Front. Oncol.

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M3814, also known as nedisertib, is a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor under phase 2 clinical trials. ABCG2 is a member of the ATP-binding cassette (ABC) transporter family that is closely related to multidrug resistance (MDR) in cancer treatment. In this study, we demonstrated that M3814 can modulate the function of ABCG2 and overcome ABCG2-mediated MDR. Mechanistic studies showed that M3814 can attenuate the efflux activity of ABCG2 transporter, leading to increased ABCG2 substrate drugs accumulation. Furthermore, M3814 can stimulate the ABCG2 ATPase activity in a concentration-dependent manner without affecting the ABCG2 protein expression or cell surface localization of ABCG2. Moreover, the molecular docking analysis indicated a high affinity between M3814 and ABCG2 transporter at the drug-binding cavity. Taken together, our work reveals M3814 as an ABCG2 modulator and provides a potential combination of co-administering M3814 with ABCG2 substrate-drugs to overcome MDR.

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“…Susan E. Bates and Robert W. Robey (NIH, Bethesda, MD). The HEK293/pcDNA3.1 and HEK293/ABCB1 cells lines were established by transfecting HEK293 cells with either the empty pcDNA3.1 vector (HEK293/pcDNA3.1) or the vector containing the full length ABCB1 DNA (HEK293/ABCB1), and were cultured in a medium containing 2 mg/mL of G418 2 weeks before conducting the experiments ( 30 ). All cell lines used in this study were within 15 to 20 passages from thawing, and were cultured at 37°C/5% CO 2 with DMEM containing 10% FBS and 1% penicillin/streptomycin.…”

Section: Methodsmentioning

confidence: 99%

Sapitinib Reverses Anticancer Drug Resistance in Colon Cancer Cells Overexpressing the ABCB1 Transporter

et al. 2020

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The efficacy of anti-cancer drugs in patients can be attenuated by the development of multi-drug resistance (MDR) due to ATP-binding cassette (ABC) transporters overexpression. In this in vitro study, we determined the reversal efficacy of the epidermal growth factor receptor (EFGR) inhibitor, saptinib, in SW620 and SW720/Ad300 colon cancer cells and HEK293/ABCB1 cells which overexpress the ABCB1 transporter. Sapitinib significantly increased the efficacy of paclitaxel and doxorubicin in ABCB1 overexpressing cells without altering the expression or the subcellular location of the ABCB1 transporter. Sapitinib significantly increased the accumulation of [ 3 H]-paclitaxel in SW620/AD300 cells probably by stimulating ATPase activity which could competitively inhibit the uptake of [ 3 H]-paclitaxel. Furthermore, sapitinib inhibited the growth of resistant multicellular tumor spheroids (MCTS). The docking study indicated that sapitinib interacted with the efflux site of ABCB1 transporter by π-π interaction and two hydrogen bonds. In conclusion, our study suggests that sapitinib surmounts MDR mediated by ABCB1 transporter in cancer cells.

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Midostaurin Reverses ABCB1-Mediated Multidrug Resistance, an in vitro Study

Cited by 27 publications

References 48 publications

Overexpression of ABCB1 Transporter Confers Resistance to mTOR Inhibitor WYE-354 in Cancer Cells

Overexpression of ABCB1 Transporter Confers Resistance to mTOR Inhibitor WYE-354 in Cancer Cells

M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells

Sapitinib Reverses Anticancer Drug Resistance in Colon Cancer Cells Overexpressing the ABCB1 Transporter

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