P=N/A, N=36, Completed, University of Edinburgh | Unknown status --> Completed

P=N/A, N=300, Completed, Baylor Research Institute | Unknown status --> Completed

The inhibitory effects of doxorubicin treatment and hypoxia on HCCO proliferation are variable, suggesting an important role of tumor-cell intrinsic properties in doxorubicin resistance. ABCB1 is a determinant of doxorubicin response in HCCOs. Combination treatment of doxorubicin and ABCB1 inhibition may increase the response rate to transarterial chemoembolization.

P=N/A, N=30, Completed, University of Edinburgh | Unknown status --> Completed

P=N/A, N=104, Completed, Tomsk National Research Medical Center of the Russian Academy of Sciences | Active, not recruiting --> Completed

This study is expected to provide valuable references and potential drugs for future research and treatment of COVID-19 and ICC.

these findings suggest that combining siRNA, doxorubicin, and vinorelbine holds promise as a therapeutic strategy to overcome ABCB1-mediated multidrug resistance in breast cancer. Further investigations and clinical trials are warranted to evaluate its clinical efficacy rigorously.

AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise.

This study showed that the ABCB1 C3435T homozygous allele genotype (TT) is associated with increased MTX-related toxicities (leukopenia, neutropenia and oral mucositis). These results may help to distinguish pediatric ALL patients with a relatively high risk of MTX-related toxicities before HD-MTX infusion and optimize MTX treatment.

The solution is to use a proper inhibitor of P-gp efflux activity to ensure the retention of the tracer inside the cells. The present study showed that Zosuquidar and Tariquidar (P-gp inhibitors) are suitable for monitoring intracellular calcium, either by flow cytometry or confocal microscopy, in cells overexpressing P-gp.

In addition, HT@ER/PTX not only inhibited P-gp-mediated removal of toxic lipid peroxidation byproducts resulting from anti-tumor drugs but also upregulated the expression of mitochondrial dynamics-related protein, fostering oxidative stress damage, which induced activation of the Caspase-3 apoptosis pathway. Our findings indicate that mitochondria targeted co-delivery of anti-tumor drugs and P-gp inhibitors could be a practical approach in treating multi-drug resistance in ABC.

This transporter-mediated restriction of brain penetration for both drugs could be almost fully inhibited by coadministration of the dual ABCB1/ABCG2 inhibitor elacridar, without signs of acute toxicity. This interaction was, however, unlikely to be mediated through any of the studied transporters or CYP3A. The obtained insights may perhaps help to further improve the safety and efficacy of entospletinib and lanraplenib.

The projection of desirable binding and effect may be procured initially by molecular docking of the inhibitor with P-gp, enabling the reduction of preliminary trials in formulation development. Here, P-gp-mediated efflux and several possible outcomes to overcome the problems associated with currently prevalent cancer treatments are highlighted.

Co-treatment with GDC-0152 restored the sensitivity to the known ABCB1 substrates, including paclitaxel, vincristine, and YM155 in ABCB1-expressing multidrug-resistant cancer cells, and it also restored the sensitivity to tamoxifen in BIRC5-overexpressing tamoxifen-resistant breast cancer cells in vitro...In conclusion, GDC-0152 has the potential for use in the management of cancer patients with ABCB1 and BIRC5-related drug resistance. The findings of our study provide essential information to physicians for designing a more patient-specific GDC-0152 clinical trial program in the future.

P2, N=300, Recruiting, Global Alliance for TB Drug Development | Not yet recruiting --> Recruiting

Co-treatment with low doses of aripiprazole sensitized MCF-7/ADR cells to VIC. Combination therapy with aripiprazole may be a valuable tool for delaying or reducing cancer recurrence by targeting P-gp-overexpressing drug-resistant breast cancer cells.

Moreover, the DEX-treated group exhibited an increase in Rho123 efflux, and it was reversed by treatment with the P-gp inhibitor verapamil or Ezr siRNA. The decrease in cell viability with paclitaxel (PTX) treatment was mitigated by pretreatment with DEX. The increased expression and activation of P-gp during the progression of lung cancer MET was regulated by Ezr. The regulatory mechanism of P-gp expression and activity may differ depending on the cell status.

Tracheal epithelial cells of GPRC5A knockout mice were much more sensitive to tariquidar and doxorubicin than those of GPRC5A wild type mice...Conclusion GPRC5A reduces lung adenocarcinoma proliferation via inhibiting ABCB1 expression. The pathway by which GPRC5A regulates ABCB1 expression needs to be investigated.

BMSC can promote the drug resistance of leukemia cells, and TET may reverse the BMSC-mediated drug resistance via inhibiting IL-6/STAT3 signaling pathway.

In most cases, the expression of Pgp increases due to increased transcription and translation, but under severe oxidative stress, it can also decrease due to the oxidation of amino acids in its molecule. At the same time, Pgp acts as a protector against oxidative stress, eliminating the causative factors and removing its by-products, as well as participating in signaling pathways.

This study provided evidence of the potential of Amaryllidaceae alkaloids as lead candidates for the development of MDR reversal agents.

With this consensus approach, 13 potential candidates were identified and then tested for their ability to inhibit P-gp, using zosuquidar, a third generation P-gp inhibitor, as a reference drug...Both retrospective and prospective results demonstrate the ability of the combined structure-based pharmacophore modeling and docking-based virtual screening approach to predict novel hit compounds with inhibitory activity toward P-gp. The resulting chemical scaffolds could serve as inspiration for the optimization of novel and more potent P-gp inhibitors.

In this study, structural modification of a third-generation P-gp inhibitor WK-X-34 based on bioisosteric and fragment-growing strategies led to the discovery of the adamantane derivative PID-9, which exhibited the best MDR reversal activity (IC50 = 0.1338 μM, RF = 78.6) in this series, exceeding those of the reported P-gp inhibitors verapamil and WK-X-34...Furthermore, the mechanism studies revealed that the reversal activity of adamantane derivatives PID-5, PID-7, and PID-9 stemmed from the inhibition of P-gp efflux. These results indicated that compound PID-9 is the most effective P-gp inhibitor among them with low toxicity and high MDR reversal activity, which provided a fundamental structural reference for further discovery of novel, effective, and non-toxic P-gp inhibitors.

Moreover, LPS activate NF-κB signal pathway, while Tet efficiently inhibited this effect.Furthermore, injection of Tet did not damage theroutineblood, liver and kidney. Retrobulbar injection of Tet significantly alleviatedLPS-induced uveitisand optic nerve injuryof rats by activating gliocyte and NF-κB signaling pathway.

Overall, our results suggest that foretinib can target MDR-linked ABCB1 and ABCG2 transporters in clinical cancer therapy.

MX106-4C selectively kills ABCB1-positive MDR colorectal cancer cells via a novel ABCB1-dependent survivin inhibition mechanism, providing a clue for designing CS compound as an alternative strategy to overcome ABCB1-mediated colorectal cancer MDR.

P2, N=170, Active, not recruiting, Cambridge University Hospitals NHS Foundation Trust | Recruiting --> Active, not recruiting

The complexes studied involve four compounds: cyclosporin A (CSA), amiodarone (AMI), pamidronate (APD), and valproic acid (VPA). Furthermore, distinctive behavior was observed in the presence of active and inactive compounds, particularly in the arrangement of ATP between NBDs, supporting the proposed nucleotide sandwich dimer mechanism for ATP binding. This study provides comprehensive insights into P-gp behavior with various ligands and ATP, offering implications for drug development, toxicity assessment and demonstrating the validity of the results derived from the MD simulations.

Furthermore, in silico docking simulations were utilized to substantiate the binding of mobocertinib within the drug-binding pockets of both ABCB1 and ABCG2. We conclude that further testing of mobocertinib in combination therapy is warranted for patients with tumors expressing elevated levels of the ABC drug transporters ABCB1 and ABCG2.

It also increased the percentage of apoptotic cells in a time-dependent manner. Moreover, a molecular docking study was carried out to explain the target compounds' potent inhibitory activity within the EGFR binding site.

In sum, we demonstrate that FN-1501 is a substrate of ABCB1 transporter from both in vivo and in vitro studies. Therefore, our findings provide new insight on the mechanism of chemoresistance due to ABCB1 overexpression.

Compounds 6g and 6i inhibited rhodamine 123 efflux in the P-gp overexpressed leukemia cells, K562/Dox, at concentrations of 0.19 µM and 0.39 µM, respectively, and increased the intracellular accumulation of doxorubicin at the submicromolar concentration of 0.098 µM...It should be noted that compounds 6g and 6i were devoid of toxic effects against peripheral blood mononuclear normal cells and erythrocytes. The data obtained indicates that both compounds might be proposed as scaffolds for obtaining promising P-gp inhibitors for overcoming MDR.

Upregulation of ABCB1 through locus amplification represents a novel, conserved mechanism of PDAC paclitaxel resistance. Kinase inhibitors identified in this study can be further (pre) clinically explored as therapeutic strategies to overcome paclitaxel resistance in PDAC.

Subsequent single-cell sequencing data confirmed that these four genes were distributed in epithelial cells, and SMR analysis revealed the causal relationship between CCNA2 and CCNB1 and the development of NSCLC. The final molecular docking and drug experiments showed that CCNA2 and CCNB1 are key targets for tetrandrine in the treatment of NSCLC.

This study comprehensively investigated PIP's inhibitory effect and mechanism on P-gp. We present a new approach for co-delivering PIP and PTX using albumin nanoparticles, which reduced toxicity and improved therapeutic efficacy both in vivo and in vitro.

P=N/A, N=77, Active, not recruiting, Jaeb Center for Health Research

P=N/A, N=130, Recruiting, Radboud University Medical Center

Lorlatinib is a net moderate inducer of P-gp and a weak inducer of CYP2B6, CYP2C9, and UGT after steady state is achieved with daily dosing. Medications that are P-gp substrates with a narrow therapeutic window should be avoided in patients taking lorlatinib; no dose modifications are needed with substrates of CYP2B6, CYP2C9, or UGT.

The metabolism features of tetrandrine and its potential antitumor mechanism were summarized, providing data for further pharmacological validation.

Our results suggest that verapamil inhibits tumor growth by modulating NFAT2 expression and enhancing tumor immune responses to PD1ab, which can be harnessed for cervical cancer therapy, especially for patients with comorbid hypertension. Indeed, further clinical trials are warranted to increase the robustness of our findings.

P2, N=30, Recruiting, Radboud University Medical Center | Trial completion date: Jun 2023 --> Jul 2025

P=N/A, N=165, Recruiting, University of Lausanne Hospitals | Trial completion date: Dec 2023 --> May 2024 | Trial primary completion date: Dec 2023 --> Mar 2024