Efflux pumps, NHE1, monocarboxylate transporters, and ABC transporter subfamily inhibitors

Mondal, Utpal K.; Ilies, Marc A.

doi:10.1016/b978-0-12-820701-7.00017-8

Cited by 2 publications

(4 citation statements)

References 158 publications

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“…We next compared the sensitizing effects of AU1 with a classical inhibitor of drug efflux, verapamil, which is clinically employed as a calcium channel blocker used to treat cardiac arrhythmias, hypertension, and angina, and is a known inhibitor of P-gp ( 49,34 ). 4T1 cells subjected to ranges of verapamil concentrations up to 5 µM appeared to grow similarly to controls, indicating that even high concentrations of verapamil had no apparent cytotoxic effect (Supplemental Figure 4).…”

Section: Evidence That Au1 Is Acting To Inhibit the Multidrug Resista...mentioning

confidence: 99%

“…Inhibition of efflux pumps such as P-gp can be achieved through interactions of the inhibitor in noncompetitive, competitive and allosteric processes, as well as through other mechanisms such as disruption of cell membrane lipid integrity and ATP hydrolysis ( 34 ). Four generations of P-gp inhibitors, categorized by metrics such as potency, selectivity, and drug interactions, have been developed and tested ( 34,37 ), but none have been approved for human use. The basis for failure of these inhibitors in clinical trials has been varied, including the necessity of utilizing intolerably high doses, high toxicity, drug interactions, and limited efficacies ( 34,37 ).…”

Section: Introductionmentioning

confidence: 99%

“…Four generations of P-gp inhibitors, categorized by metrics such as potency, selectivity, and drug interactions, have been developed and tested ( 34,37 ), but none have been approved for human use. The basis for failure of these inhibitors in clinical trials has been varied, including the necessity of utilizing intolerably high doses, high toxicity, drug interactions, and limited efficacies ( 34,37 ). Nevertheless, efforts have continued to explore the use of natural and/or FDA-approved compounds which demonstrate P-gp inhibition activity for adjunctive therapeutic use with chemotherapy ( [38][39][40] ).…”

Section: Introductionmentioning

confidence: 99%

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A Bptf Inhibitor That Interferes with the Multidrug Resistance Pump to Sensitize Triple Negative Breast Cancer Cells to Chemotherapy

Sinanian,

Rahman,

Elshazly

et al. 2024

Preprint

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Triple negative breast cancer (TNBC) is associated with a generally poor prognosis due to its highly aggressive and metastatic nature, lack of targetable receptors, as well as the frequent development of resistance to chemotherapy. We previously reported that AU1, a small molecule developed as an inhibitor of BPTF (bromodomain PHD finger containing transcription factor), was capable of sensitizing preclinical models of triple negative breast cancer to chemotherapy, in part via the promotion of autophagy. In studies reported here, we identify an additional property of this compound, specifically that sensitization is associated with inhibition of the P-glycoprotein efflux pump. In silico molecular docking studies indicate that AU1 binds to active regions of the efflux pump, in a manner consistent with inhibition of pump function. This work identifies a novel chemical structure that can influence multidrug efflux, an established mechanism of drug resistance in triple negative breast cancer, that has not yet been successfully addressed by clinical efforts.

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Section: Evidence That Au1 Is Acting To Inhibit the Multidrug Resista...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Bptf Inhibitor That Interferes with the Multidrug Resistance Pump to Sensitize Triple Negative Breast Cancer Cells to Chemotherapy

Sinanian,

Rahman,

Elshazly

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…Tumor acidification was shown to induce immunosuppression and to contribute significantly to resistance to chemotherapy and radiotherapy [ 6 , 9 , 13 , 14 , 15 ]. CA IX and CA XII expressions were correlated with poor prognosis in many cancers [ 4 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

PEG Linker Length Strongly Affects Tumor Cell Killing by PEGylated Carbonic Anhydrase Inhibitors in Hypoxic Carcinomas Expressing Carbonic Anhydrase IX

Mondal

Doroba

Shabana

et al. 2021

IJMS

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Hypoxic tumors overexpress membrane-bound isozymes of carbonic anhydrase (CA) CA IX and CA XII, which play key roles in tumor pH homeostasis under hypoxia. Selective inhibition of these CA isozymes has the potential to generate pH imbalances that can lead to tumor cell death. Since these isozymes are dimeric, we designed a series of bifunctional PEGylated CA inhibitors (CAIs) through the attachment of our preoptimized CAI warhead 1,3,4-thiadiazole-2-sulfonamide to polyethylene glycol (PEG) backbones with lengths ranging from 1 KDa to 20 KDa via a succinyl linker. A detailed structure−thermal properties and structure–biological activity relationship study was conducted via differential scanning calorimetry (DSC) and via viability testing in 2D and 3D (tumor spheroids) cancer cell models, either CA IX positive (HT-29 colon cancer, MDA-MB 231 breast cancer, and SKOV-3 ovarian cancer) or CA IX negative (NCI-H23 lung cancer). We identified PEGylated CAIs DTP1K 28, DTP2K 23, and DTP3.4K 29, bearing short and medium PEG backbones, as the most efficient conjugates under both normoxic and hypoxic conditions, and in the tumor spheroid models. PEGylated CAIs did not affect the cell viability of CA IX-negative NCI-H23 tumor spheroids, thus confirming a CA IX-mediated cell killing for these potential anticancer agents.

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Efflux pumps, NHE1, monocarboxylate transporters, and ABC transporter subfamily inhibitors

Cited by 2 publications

References 158 publications

A Bptf Inhibitor That Interferes with the Multidrug Resistance Pump to Sensitize Triple Negative Breast Cancer Cells to Chemotherapy

A Bptf Inhibitor That Interferes with the Multidrug Resistance Pump to Sensitize Triple Negative Breast Cancer Cells to Chemotherapy

PEG Linker Length Strongly Affects Tumor Cell Killing by PEGylated Carbonic Anhydrase Inhibitors in Hypoxic Carcinomas Expressing Carbonic Anhydrase IX

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