Ciprofloxacin Enhances the Chemosensitivity of Cancer Cells to ABCB1 Substrates

Gupta, Pranav; Gao, Hailing; Ashar, Yunali V.; Karadkhelkar, Nishant; Yoganathan, Sabesan; Chen, Zhe‐Sheng

doi:10.3390/ijms20020268

Cited by 30 publications

(31 citation statements)

References 40 publications

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“…Furthermore, it is likely that the effects of quinazoline-based EGFR inhibitors, including sapitinib, on ABC transporters, are due to their structures, indicating that certain structures inhibit the efflux function of ABC transporters. However, we cannot rule out the possibility that the increase in anticancer drug efficacy produced by sapitinib could be due to its inhibition of tyrosine kinases ( 52 , 53 ). Finally, sapitinib did not significantly alter the cytotoxic efficacy of cisplatin and oxaliplatin, two anti-cancer drugs that are not substrates for the ABCB1 transporter ( 42 ).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…Among them, ABCB1 (P-gp, MDR1) and ABCG2 (breast cancer resistance protein, BCRP) have been identified as the major contributor to MDR in variety of cancers (3,(9)(10)(11). Many studies suggested that the overexpression of ABCB1 and ABCG2 cause reduction of intracellular drugs (12)(13)(14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Erdafitinib Antagonizes ABCB1-Mediated Multidrug Resistance in Cancer Cells

Feng

Zhang

et al. 2020

Front. Oncol.

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ABCB1 overexpression is known to contribute to multidrug resistance (MDR) in cancers. Therefore, it is critical to find effective drugs to target ABCB1 and overcome MDR. Erdafitinib is a tyrosine kinase inhibitor (TKI) of fibroblast growth factor receptor (FGFR) that is approved by the FDA to treat urothelial carcinoma. Previous studies have demonstrated that some TKIs exhibit MDR reversal effect. In this work, we examined whether erdafitinib could reverse MDR mediated by ABCB1. The results of reversal experiments showed that erdafitinib remarkably reversed ABCB1-mediated MDR without affecting ABCG2-mediated MDR. The results of immunofluorescence and Western blot analysis demonstrated that erdafitinib did not affect the expression of ABCB1 or its cellular localization. Further study revealed that erdafitinib inhibited ABCB1 efflux function leading to increasing intracellular drug accumulation, thereby reversing MDR. Furthermore, ATPase assay indicated that erdafitinib activated the ABCB1 ATPase activity. Docking study suggested that erdafitinib interacted with ABCB1 on the drug-binding sites. In summary, this study demonstrated that erdafitinib can reverse MDR mediated by ABCB1, suggesting that combination of erdafitinib and ABCB1-substrate conventional chemotherapeutic drugs could potentially be used to overcome MDR mediated by ABCB1.

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“…Beside the development of special P-gp regulators, drug repurposing has emerged as another appealing strategy as those molecules have been assessed in clinical/preclinical trials and considered as safe enough [36,37]. Many small molecular drugs, including TKIs [38], phosphodiesterase inhibitors [39], and fluoroquinolone antibiotics [40], antagonize P-gp mediated MDR at non-cytotoxic concentrations. These studies provide important information for future clinical trials and for further new drugs targeting P-gp.…”

Section: Discussionmentioning

confidence: 99%

“…MK-8776 exhibited similar effects to these three drugs in HEK293/ ABCB1 cells, which are normal cell lines that were transfected with ABCB1 ; meanwhile, it exhibited no such effects to the non-Pgp substrate cisplatin, indicating its effects in modulating P-gp functions. As we can observe, since all cells expressed a high level of P-gp [40], the RF of the chemotherapeutics and the reversal effects by MK-8776 in KB-C2 or SW620/Ad300 cells and HEK293/ ABCB1 cells were different. The RF in KB-C2 or SW620/Ad300 cells were higher than in HEK293/ ABCB1 cells, and the reversal effects of MK-8776 and verapamil in KB-C2 or SW620/Ad300 cells were weaker than in HEK293/ ABCB1 cells.…”

Section: Discussionmentioning

confidence: 99%

Chk1 Inhibitor MK-8776 Restores the Sensitivity of Chemotherapeutics in P-glycoprotein Overexpressing Cancer Cells

Cui

Cai

Wang

et al. 2019

IJMS

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P-glycoprotein (P-gp), which is encoded by the ATP-binding cassette (ABC) transporter subfamily B member 1 (ABCB1) gene, is one of the most pivotal ABC transporters that transport its substrates across the cell membrane. Its overexpression is one of the confirmed causes of multidrug resistance (MDR), which results in the failure of cancer treatment. Here, we report that checkpoint kinase (Chk) 1 inhibitor MK-8776, a drug candidate in clinical trial, can restore the sensitivity of chemotherapeutics that are substrates of P-gp in KB-C2, SW620/Ad300 cells and human embryonic kidney (HEK)293/ABCB1 cells that overexpress P-gp. MK-8776 remarkably enhanced the cellular [3H]-paclitaxel accumulation and suppressed the efflux function of P-gp without reducing its expression and affecting its cellular localization in cancer cells. Furthermore, MK-8776 (0–40 μM) stimulated the activity of ATPase in P-gp, which was 4.1-fold greater than the control. In addition, MK-8776 formed a cation–π bond and π–π interaction with key residues of the substrate-binding site in P-gp, as indicated by computer-aided molecular docking study. Our study indicated that MK-8776 may significantly enhance the sensitivity of chemotherapeutics that are substrates of P-gp, providing important information for its application in the reversal of MDR.

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Ciprofloxacin Enhances the Chemosensitivity of Cancer Cells to ABCB1 Substrates

Cited by 30 publications

References 40 publications

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

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

Erdafitinib Antagonizes ABCB1-Mediated Multidrug Resistance in Cancer Cells

Chk1 Inhibitor MK-8776 Restores the Sensitivity of Chemotherapeutics in P-glycoprotein Overexpressing Cancer Cells

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