VS-4718 Antagonizes Multidrug Resistance in ABCB1- and ABCG2-Overexpressing Cancer Cells by Inhibiting the Efflux Function of ABC Transporters

Ji, Ning; Yang, Yuqi; Cai, Chao-Yun; Lei, Zi‐Ning; Wang, Jing-Quan; Gupta, Pranav; Teng, Quincy; Chen, Zhe‐Sheng; Yang, Dong‐Hua

doi:10.3389/fphar.2018.01236

Cited by 43 publications

(35 citation statements)

References 45 publications

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“…In order to understand the mechanism by which ciprofloxacin sensitizes the ABCB1-overexpressing cells to the substrates of ABCB1, we assessed the effects of ciprofloxacin on the intracellular accumulation and efflux of [ 3 H]-paclitaxel. Consistent with previous studies, our findings indicated that ciprofloxacin produces a significant concentration-dependent increase in the intracellular accumulation of [ 3 H]-paclitaxel in cells expressing ABCB1 [32,33,34]. Furthermore, ciprofloxacin produces a significant concentration-dependent decrease in the efflux of [ 3 H]-paclitaxel from cells overexpressing the ABCB1 transporter.…”

Section: Discussionsupporting

confidence: 91%

Ciprofloxacin Enhances the Chemosensitivity of Cancer Cells to ABCB1 Substrates

Gupta

Gao

Ashar

et al. 2019

IJMS

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ABCB1 is one of the major drug efflux transporters that is known to cause multidrug resistance (MDR) in cancer patients receiving chemotherapy for the treatment of solid tumors and hematological malignancies. Inhibition of ABCB1 efflux function is important for maintaining the intracellular concentration of chemotherapeutic drugs. Here, we evaluated ciprofloxacin for its ability to reverse MDR caused by the overexpression of ABCB1. Cytotoxicity of ciprofloxacin was determined by the MTT assay. The chemosensitizing effects of ciprofloxacin were determined in combination with ABCB1 substrates. The intracellular accumulation and efflux of ABCB1 substrates was measured by a scintillation counter, and protein expression was determined by the Western blotting. Vanadate-sensitive ATPase assay was performed to determine the effect of ciprofloxacin on the ATPase activity of ABCB1, and docking analysis was done to determine the interaction of ciprofloxacin with ABCB1. Ciprofloxacin significantly potentiated the cytotoxic effects of ABCB1 substrates in ABCB1-overexpressing cells. Furthermore, ciprofloxacin increased the intracellular accumulation and decreased the efflux of [3H]-paclitaxel without altering the expression of ABCB1. Ciprofloxacin stimulated the ATPase activity of ABCB1 in a concentration-dependent manner. Our findings showed that ciprofloxacin potently inhibits the ABCB1 efflux function and it has potential to be developed as a combination anticancer therapy.

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Section: Discussionsupporting

confidence: 91%

Ciprofloxacin Enhances the Chemosensitivity of Cancer Cells to ABCB1 Substrates

Gupta

Gao

Ashar

et al. 2019

IJMS

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“…The Western blotting protocol has been described in a previous publication [52] with minor modifications. Cells were incubated with or without venetoclax for 0, 24, 48, or 72 h. Corresponding cells were lysed at each time point and lysates were stocked at −80 • C before the protein amount was quantified using BCA protein assay kit (Pierce, IL, USA).…”

Section: Western Blottingmentioning

confidence: 99%

Venetoclax, a BCL-2 Inhibitor, Enhances the Efficacy of Chemotherapeutic Agents in Wild-Type ABCG2-Overexpression-Mediated MDR Cancer Cells

Wang

Teng

et al. 2020

Cancers

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Previous studies have shown that small-molecule BCL-2 inhibitors can have a synergistic interaction with ABCG2 substrates in chemotherapy. Venetoclax is a potent and selective BCL-2 inhibitor, approved by the FDA in 2016 for the treatment of patients with chronic lymphocytic leukemia (CLL). This study showed that, at a non-toxic concentration, venetoclax at 10 µM significantly reversed multidrug resistance (MDR) mediated by wild-type ABCG2, without significantly affecting MDR mediated by mutated ABCG2 (R482G and R482T) and ABCB1, while moderate or no reversal effects were observed at lower concentrations (0.5 to 1 µM). The results showed that venetoclax increased the intracellular accumulation of chemotherapeutic agents, which was the result of directly blocking the wild-type ABCG2 efflux function and inhibiting the ATPase activity of ABCG2. Our study demonstrated that venetoclax potentiates the efficacy of wild-type ABCG2 substrate drugs. These findings may provide useful guidance in combination therapy against wild-type ABCG2-mediated MDR cancer in clinical practice.

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“…In our study, NVP-CGM097 stimulated ABCB1-ATPase when the concentration is lower than 10 μM and inhibited ABCB1-associated ATPase at higher concentration of NVP-CGM097. Previous studies have also shown that some ABCB1 inhibitors could either stimulate ( 45 ), inhibit ( 46 ), or show stimulatory effect at lower concentration while inhibitory effect at higher concentration ( 47 ). Such discrimination in ABCB1 inhibitors were explained recently by Alam et al through a set of substrate- and inhibitor-binding human ABCB1 cryo-EM protein models ( 35 ).…”

Section: Discussionmentioning

confidence: 98%

NVP-CGM097, an HDM2 Inhibitor, Antagonizes ATP-Binding Cassette Subfamily B Member 1-Mediated Drug Resistance

et al. 2020

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Multidrug resistance (MDR) is a major challenge in the treatment of tumors. It refers to cancer cells become resistant to not only the therapeutic drug, but also cross-resistant to multiple drugs with distinct structures and mechanisms of action when they are exposed to a drug for a period of time. An essential mechanism of MDR is the aberrant expression and function of ATP-binding cassette (ABC) transporters. Therefore, blocking the function of ABC transporters has the therapeutic potential in reversing MDR. The hdm2 oncogene product, HDM2 (also known as MDM2), is an important negative regulator of the p53 tumor suppressor. NVP-CGM097 is an HDM2 inhibitor that can inhibit the proliferation of tumor cells and is currently under clinical trials. In this study, we evaluate whether NVP-CGM097 could reverse ABCB1-mediated MDR. The results of reversal experiment showed that NVP-CGM097 remarkably reversed ABCB1-mediated MDR but not ABCG2-mediated MDR. The results of Western blot and immunofluorescence suggested that the level of expression and subcellular localization of ABCB1 protein were not significantly altered by NVP-CGM097. Mechanism studies indicated that NVP-CGM097 could reverse ABCB1-mediated MDR by directly blocking the ABCB1-mediated drug efflux and raising the accumulation of chemotherapeutic drugs in cancer cells. ATPase analysis showed that low concentration NVP-CGM097 activates ABCB1 ATPase activity while high concentration NVP-CGM097 inhibited ABCB1-associated ATPase. Docking study indicated that NVP-CGM097 tended to bind to the inhibitory site, which led to slight but critical conformational changes in the transporter and reduced the ATPase activity. Overall, our study demonstrates that NVP-CGM097 can be used in conjunction with chemotherapeutic drugs to counteract MDR and improve the antitumor responses.

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VS-4718 Antagonizes Multidrug Resistance in ABCB1- and ABCG2-Overexpressing Cancer Cells by Inhibiting the Efflux Function of ABC Transporters

Cited by 43 publications

References 45 publications

Ciprofloxacin Enhances the Chemosensitivity of Cancer Cells to ABCB1 Substrates

Ciprofloxacin Enhances the Chemosensitivity of Cancer Cells to ABCB1 Substrates

Venetoclax, a BCL-2 Inhibitor, Enhances the Efficacy of Chemotherapeutic Agents in Wild-Type ABCG2-Overexpression-Mediated MDR Cancer Cells

NVP-CGM097, an HDM2 Inhibitor, Antagonizes ATP-Binding Cassette Subfamily B Member 1-Mediated Drug Resistance

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