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Multidrug resistance (MDR) remains a significant obstacle in cancer treatment, primarily attributable to the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCG2 within cancer cells. These transporters actively diminish the effectiveness of cytotoxic drugs by facilitating ATP hydrolysis-dependent drug efflux, thereby reducing intracellular drug accumulation. Given the absence of approved treatments for multidrug-resistant cancers and the established benefits of combining tyrosine kinase inhibitors (TKIs) with conventional anticancer drugs, we investigate the potential of vodobatinib, a potent c-Abl TKI presently in clinical trials, to restore sensitivity to chemotherapeutic agents in multidrug-resistant cancer cells overexpressing ABCB1 and ABCG2. Results indicate that vodobatinib, administered at sub-toxic concentrations, effectively restores the sensitivity of multidrug-resistant cancer cells to cytotoxic drugs in a concentration-dependent manner. Moreover, vodobatinib enhances drug-induced apoptosis in these cells by inhibiting the drug-efflux function of ABCB1 and ABCG2, while maintaining their expression levels. Moreover, we found that while vodobatinib enhances the ATPase activity of ABCB1 and ABCG2, the overexpression of these transporters does not induce resistance to vodobatinib. These results strongly suggest that increased levels of ABCB1 or ABCG2 are unlikely to play a significant role in the development of resistance to vodobatinib in cancer patients. Overall, our findings unveil an additional pharmacological facet of vodobatinib against ABCB1 and ABCG2 activity, suggesting its potential incorporation into combination therapy for a specific subset of patients with tumors characterized by high ABCB1 or ABCG2 levels. Further investigation is warranted to fully elucidate the clinical implications of this therapeutic approach., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: Atrial fibrillation (AF) is a prevalent clinical condition worldwide, with a high global incidence that significantly impacts disease burden and mortality rates. Single nucleotide polymorphisms in ABCB1 and ABCG2 are common, but the clinical outcomes are poorly understood. This study examines the association between the genetic variations of ABCB1 and ABCG2 and the risk of AF in a Taiwanese population., Methods and Results: This case-control study recruited 216 AF patients from two hospitals in Taiwan between 2021 and 2023. Control groups were matched by age (± one year), gender, and AF-related variables from the Taiwan Biobank. Logistic regression analyzed the association between three genetic variants and AF risk. A significant association was noted between ABCG2 rs2231142 and AF risk. Those with ABCG2 rs2231142 G/T and T/T genotypes had a 1.91-fold (95 % CI = 1.04-3.53) increased risk of AF compared to those with the G/G genotype. This association was particularly pronounced in males in those carrying ABCG2 rs2231143 T/T genotype having a 4.47-fold (95 % CI = 1.02-19.67) increased risk after adjusting for covariates. There were no overall significant associations between AF risk and the polymorphisms of ABCB1 rs4148738 and rs1128503., Conclusion: A robust risk association between the ABCG2 rs2231142 T allele and AF in Asian populations, particularly in male adults, suggests that genetic testing for this polymorphism could be integrated into risk assessment models for AF., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Clozapine (CLZ) is an antipsychotic which is particularly used in treatment resistant schizophrenia patients who do not respond to other agents. It is preferred because it reduces suicidal behaviours and attempts, reducing aggression and violent behaviour. The aim of the study is to evaluate the effects of ABCB1 rs1045642 and UGT1A4 rs2011425 polymorphisms on CLZ and its major metabolite N- desmethly clozapine (DCLZ) plasma concentrations in patients with schizophrenia. A total 109 of Turkish patients with schizophrenia on continually administered CLZ monotherapy were included. The plasma concentrations of CLZ and DCLZ were measured using an HPLC after liquid-liquid extraction while, transporter gene ABCB1 and phase two enzyme UGT1A4 polymorphisms were identified using PCR- RFLP method. Results showed that UGT1A4*3 polymorphism has statistically significant effects on CLZ C/D and DCLZ C/D levels in patients with sub/supra therapeutic levels while ABCB1 C3435T polymorphism has a significant effect on CLZ/DCLZ ratio among patients who have subtherapeutic levels. This study indicates the influence of genetic differences on plasma levels and highlights the importance of pharmacogenetic studies in clinic. Using the obtained results as pharmacogenetic biomarkers will help clinicians provide effective treatment in individual patients and reduce the undesirable side effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Background: Macrolides are widely used antibiotics, but adverse drug reactions (ADRs), particularly in genetically predisposed individuals, can compromise their safety. This study examines the impact of pharmacogenetic markers on macrolide safety in participants with bacterial complications of influenza., Objective: To evaluate how polymorphisms in genes encoding transporter proteins (ABCB1) and enzymes (CYP3A4, CYP3A5) influence ADR risk during macrolide therapy., Methods: A prospective study included 100 participants with lower respiratory tract bacterial complications of influenza treated with azithromycin or erythromycin for five days. Genotyping targeted ABCB1 (3435C>T) , CYP3A4 (C>T intron 6) , and CYP3A5 (6986A>G) polymorphisms. ADRs were monitored daily and correlated with genetic markers., Results: The ABCB1 (3435C>T) polymorphism was associated with higher rates of abdominal pain and diarrhea in CT and TT genotypes (OR = 2.12, p  = 0.043). The CYP3A4 (C>T intron 6) polymorphism increased ADR risk in erythromycin-treated participants (OR = 24.0, p  = 0.0339). No significant effects were observed for CYP3A5 (6986A>G)., Conclusion: Genetic polymorphisms in ABCB1 and CYP3A4 genes predict macrolide-related ADRs. Pharmacogenetic screening could improve macrolide safety, particularly for genetically susceptible individuals.

The aim of our study was to investigate the role of ABCB1 polymorphism in the pharmacokinetics of carbamazepine (CBZ) in children. The study enrolled 47 Serbian pediatric epileptic patients on CBZ treatment. Genotyping for ABCB1 1236C

Brassinosteroids (BRs) are steroidal phytohormones indispensable for plant growth, development, and responses to environmental stresses. The export of bioactive BRs to the apoplast is essential for BR signaling initiation, which requires binding of a BR molecule to the extracellular domains of the plasma membrane-localized receptor complex. We have previously shown that the Arabidopsis thaliana ATP-binding cassette (ABC) transporter ABCB19 functions as a BR exporter and, together with its close homolog ABCB1, positively regulates BR signaling. Here, we demonstrate that ABCB1 is another BR transporter. The ATP hydrolysis activity of ABCB1 can be stimulated by bioactive BRs, and its transport activity was confirmed in proteoliposomes and protoplasts. Structures of ABCB1 were determined in substrate-unbound (apo), brassinolide (BL)-bound, and ATP plus BL-bound states. In the BL-bound structure, BL is bound to the hydrophobic cavity formed by the transmembrane domain and triggers local conformational changes. Together, our data provide additional insights into ABC transporter-mediated BR export., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: ABCB1 overexpression is a key factor in causing multidrug resistance (MDR). As a result, it is crucial to discover effective medications against ABCB1 to overcome MDR. Falnidamol, a tyrosine kinase inhibitor (TKI) targeting the epidermal growth factor receptor (EGFR), is currently in phase 1 clinical trials for the treatment of solid tumors. In this work, we assessed whether falnidamol could act as an inhibitor of ABCB1 to reverse ABCB1-mediated MDR., Methods: The reversal effect of falnidamol on MDR was assessed by MTT, colony formation, 3D microsphere, and xenograft model assays. The protein expression or cellular localization was tested by western blot and immunofluorescence analysis. The intracellular doxorubicin accumulation and efflux were assessed by flow cytometry. The ATPase activity of ABCB1 was detected by a microplate reader. The interaction between falnidamol and ABCB1 was evaluated by docking analysis and cellular thermal shift assay., Results: Our data showed that falnidamol specifically reversed ABCB1-mediated MDR but not ABCG2-mediated MDR in vitro and in vivo. Mechanistic studies suggested falnidamol had no effect on ABCB1 expression or cellular localization, nor on the AKT or ERK pathways. Further studies found that falnidamol reduced ABCB1's efflux function, resulting in enhanced intracellular agent accumulation and thus overcoming MDR. ATPase assay showed that falnidamol suppressed the ABCB1 ATPase activity. Furthermore, docking analysis and cellular thermal shift assay indicated that falnidamol bound directly to the drug-binding site of ABCB1 transporter., Conclusion: The present study proves that falnidamol acts as a highly potent and specific active ABCB1 transporter inhibitor, and can reverse ABCB1-mediated MDR, implying that combining falnidamol with ABCB1 substrate chemotherapeutic agents has the potential to overcome ABCB1-mediated MDR., Competing Interests: Declarations. Ethical approval: The animal study protocol was approved by the Animal Ethics Committee of Shandong Second Medical University (2021SDL378, Weifang, China). The guidelines include animal care, housing, and procedures that minimize the suffering and distress of animals. Strict adherence to the ARRIVE guidelines was observed throughout all of the procedures carried out during the research to ensure that the animals received the best possible care. Moreover, all procedures were conducted ethically and humanely at all times. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

This study investigated the potential of MET kinase inhibitors, cabozantinib, crizotinib, and PHA665752, in reversing multidrug resistance (MDR) mediated by ABCB1 in cancer cells. The accumulation of the fluorescent probe, Rhodamine 123, was assessed using flow cytometry and fluorescence microscopy in MDR MES-SA/DX5 and parental cells. The growth inhibitory activity of MET inhibitors as monotherapies and in combination with chemotherapeutic drugs was evaluated by MTT assay. CalcuSyn software was used to analyze the combination index (CI) as an index of drug-drug interaction in combination treatments. Results showed that at concentrations of 5, and 25 μM, c-MET inhibitors significantly increased Rhodamine 123 accumulation in MDR cells, with ratios up to 17.8 compared to control cells, while exhibiting no effect in parental cells. Additionally, the combination of c-MET inhibitors with the chemotherapeutic agent doxorubicin synergistically enhanced cytotoxicity in MDR cells, as evidenced by combination index (CI) values of 0.54 ± 0.08, 0.69 ± 0.1, and 0.85 ± 0.07 for cabozantinib, crizotinib, and PHA665752, respectively. While all three c-MET inhibitors stimulated ABCB1 ATPase activity in different manners at certain concentrations, PHA-665752 suppressed it at high concentration. In silico analysis also suggested that the transmembrane domains (TMD) of ABCB1 transporters could be considered potential target for these agents. Our results suggest that c-MET inhibitors can serve as promising MDR reversal agents in ABCB1-medicated drug-resistant cancer cells., Competing Interests: Conflict of interestThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© King Abdulaziz City for Science and Technology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Arsenic (As) can penetrate brain tissue through the blood-brain barrier (BBB), and the ATP-binding cassette subfamily B member 1 (Abcb1) has been shown to facilitate the transport of inorganic arsenic (iAs) in animal liver, small intestine, and yeast. However, the relationship between Abcb1 and BBB has not been reported, and the mechanism of brain microvascular endothelial cells Abcb1 on the transport of iAs needs to be further studied. Increased arsenic levels were observed in mice exposed to 25 mg/L or 50 mg/L of sodium arsenite (NaAsO 2 ) in drinking water, and both arsenic uptake and efflux were detected in bEnd.3 cells treated with 16 μmol/L NaAsO 2 . Elevated levels of Abcb1 protein were found in the NaAsO 2 -exposed mouse brain microvascular endothelium and in NaAsO 2 -treated bEnd.3 cells. Inhibition of Abcb1's efflux function significantly reduced the 2-hour arsenic efflux rate in bEnd.3 cells loaded arsenic. Conversely, overexpression of either Abcb1a or Abcb1b significantly increased the 2-hour arsenic efflux rate in these cells loaded arsenic. These findings suggest that Abcb1 may play a crucial role in mediating arsenic efflux from mouse brain microvascular endothelial cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Acute lymphocytic leukemia (ALL), characterized by uncontrolled growth of abnormal lymphocytes, predominantly affects children. Genetic analysis focusing on genes and microRNAs reveals important information about the biology of ALL, enabling accurate diagnosis and treatment. This study examines gene and microRNA expression in B cell ALL to improve early diagnosis and personalized treatment., Methods: Bone marrow samples were collected from patients both before and after the induction phase of chemotherapy. Comprehensive diagnostic techniques including flow cytometry, molecular assays, real-time PCR for common translocations, karyotyping, and complete blood count (CBC) analysis were employed. These methods were utilized to determine the type and risk assessment of ALL, identify specific gene and microRNA expressions, and measure blood cell counts., Results: The study comprised 12 patients, all under the age of 18. Post-treatment RT-PCR analysis revealed significant reductions in the expression of the ABCB1 gene, miR-129-5p, and miR-9-5p following the induction phase of chemotherapy. Karyotype analysis indicated that two patients were hypodiploid; unfortunately, both of these patients did not survive., Conclusion: MicroRNAs and ABC genes serve as predictive and prognostic biomarkers in Acute Lymphoblastic Leukemia (ALL) and should be carefully reconsidered. It is more accurate to state that while microRNAs and ABC genes may potentially influence treatment response in ALL, further research is crucial to fully understand their roles in determining treatment outcomes., (© 2024 The Author(s). Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Background: The high invasion and heterogeneity of head and neck squamous cell carcinoma (HNSCC) commonly leads to poor clinical outcomes. Identification of reliable biomarkers for HNSCC is imperative., Methods: The targeted gene with the highest mutation was screened out in cBioPortal database, and the interactive microRNAs (miRNAs) were identified by miRNA-mRNA co-expression analysis. CCK-8 and transwell assays were used to explore the proliferative, migrative, and invasive behaviors of HNSCC cells. The dual-luciferase reporter assay and cell transfection experiment were conducted. The role of miR-15a-5p was investigated in the in vivo xenograft mouse model., Results: ATP binding cassette transporter 1 (ABCB1) had the highest mutation frequency and multiple mutation types in HNSCC, and the decreased ABCB1 was significantly related to better prognosis of HNSCC patients. MiR-15a-5p was a regulator for ABCB1, which was up-regulated after miR-15a-5p inhibition in vitro . Furthermore, the miR-15a-5p knockdown significantly suppressed HNSCC cell proliferation, migration, and invasion in vitro , and reduced the HNSCC tumor growth and migration capabilities in vivo , possibly through NF-κB signaling pathway., Conclusion: Collectively, miR-15a-5p knockdown increased the ABCB1 level and abated the HNSCC progression via the NF-κB signaling pathway. ABCB1 and miR-15a-5p were underlying predictors for HNSCC therapeutic biomarkers.

Purpose: The impact of genetic polymorphisms in the ABCB1 and CES1 genes on dabigatran plasma concentrations remains a subject of debate, and the purpose of this study was to quantitatively assess the effects of genetic polymorphisms on dabigatran esters in healthy Chinese subjects employed a population pharmacokinetic (PopPK) approach., Methods: In total, 1,926 pharmacokinetic (PK) samples from 123 healthy individuals who were given 150 mg of dabigatran orally during a fasting state or postprandially were analyzed using the PopPK model. A two-compartment model with first-order absorption was found to adequately describe the PK data., Results: The results showed that covariates food intake and ABCB1 SNP rs4148738 were shown to have statistically significant impacts. Specifically, in postprandial administration increased lag time (ALAG) and clearance (CL) by 2.65% and 0.51%, respectively, and decreased absorption rate constant (KA) by 0.24%. Additionally, in subjects with CT genotype ABCB1 (rs4148738), the central ventricular volume of distribution (V 2 ) was increased by 0.38%., Conclusion: In summary, the PopPK model developed in this study was robust and effectively characterized the pharmacokinetics of dabigatran in healthy Chinese adults, demonstrating that both food and ABCB1 genetic variation significantly influence the absorption and plasma concentration levels of dabigatran., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yang, Tan, Li, Wang, Liu, Chen, Zhou, Zeng, Zeng, Xiong, Zhang, Li, Du, Liu, Chen and He.)

The emergence of multidrug resistance (MDR) in malignant tumors is one of the major threats encountered currently by many chemotherapeutic agents. Among the various mechanisms involved in drug resistance, P-glycoprotein (P-gp, ABCB1), a member of the ABC transporter family that significantly increases the efflux of various anticancer drugs from tumor cells, and the metabolic enzyme CYP1B1 are widely considered to be two critical targets for overcoming MDR. Unfortunately, no MDR modulator has been approved by the FDA to date. In this study, based on pharmacophore hybridization, bioisosteric and fragment-growing strategies, we designed and synthesized 11 novel tetrahydroisoquinoline-benzo[h]chromen-4-one conjugates as dual ABCB1/CYP1B1 inhibitors. Among them, the preferred compound A10 exhibited the best MDR reversal activity (IC 50  = 0.25 μM, RF = 44.4) in SW620/AD300 cells, being comparable to one of the most potent third-generation P-gp inhibitors WK-X-34. In parallel, this dual ABCB1/CYP1B1 inhibitory effect drives compound A10 exhibiting prominent drug resistance reversal activity to doxorubicin (IC 50  = 4.7 μM, RF = 13.7) in ABCB1/CYP1B1-overexpressing DOX-SW620/AD300-1B1 resistant cells, which is more potent than that of the CYP1B1 inhibitor ANF. Furthermore, although compound A2 possessed moderate ABCB1/CYP1B1 inhibitory activity, it showed considerable antiproliferative activity towards drug-resistant SW620/AD300 and MKN45-DDP-R cells, which may be partly related to the increase of PUMA expression to promote the apoptosis of the drug-resistant MKN45-DDP-R cells as confirmed by proteomics and western blot assay. These results indicated that the tetrahydroisoquinoline-benzo[h]chromen-4-one conjugates may provide a fundamental scaffold reference for further discovery of MDR reversal agents., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jinyun Dong reports financial support was provided by the National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The P-glycoprotein (ABCB1)-mediated multidrug resistance (MDR) has emerged as a significant impediment to the efficacy of cancer chemotherapy in clinical therapy, which could promote the development of effective agents for MDR reversal. In this work, we reported the exploration of novel pyrazolo [1,5-a]pyrimidine derivatives as potent reversal agents capable of enhancing the sensitivity of ABCB1-mediated MDR MCF-7/ADR cells to paclitaxel (PTX). Among them, compound 16q remarkably increased the sensitivity of MCF-7/ADR cells to PTX at 5 μM (IC 50  = 27.00 nM, RF = 247.40) and 10 μM (IC 50  = 10.07 nM, RF = 663.44). Compound 16q could effectively bind and stabilize ABCB1, and does not affect the expression and subcellular localization of ABCB1 in MCF-7/ADR cells. Compound 16q inhibited the function of ABCB1, thereby increasing PTX accumulation, and interrupting the accumulation and efflux of the ABCB1-mediated Rh123, thus resulting in exhibiting good reversal effects. In addition, due to the potent reversal effects of compound 16q, the abilities of PTX to inhibit tubulin depolymerization, and induce cell cycle arrest and apoptosis in MCF-7/ADR cells under low-dose conditions were restored. These results indicate that compound 16q might be a promising potent reversal agent capable of revising ABCB1-mediated MDR, and pyrazolo [1,5-a]pyrimidine might represent a novel scaffold for the discovery of new ABCB1-mediated MDR reversal agents., Competing Interests: Declaration of competing interest The authors declared that there was no conflict of interest about this work., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The intracellular distribution and transportation process are essential for maintaining PD-L1 (programmed death-ligand 1) expression, and intervening in this cellular process may provide promising therapeutic strategies. Here, through a cell-based high content screening, it is found that the ABCB1 (ATP binding cassette subfamily B member 1) modulator zosuquidar dramatically suppresses PD-L1 expression by triggering its autophagic degradation. Mechanistically, ABCB1 interacts with PD-L1 and impairs COP II-mediated PD-L1 transport from ER (endoplasmic reticulum) to Golgi apparatus. The treatment of zosuquidar enhances ABCB1-PD-L1 interaction and leads the ER retention of PD-L1, which is subsequently degraded in the SQSTM1-dependent selective autophagy pathway. In CT26 mouse model and a humanized xenograft mouse model, zosuquidar significantly suppresses tumor growth and accompanies by increased infiltration of cytotoxic T cells. In summary, this study indicates that ABCB1 serves as a negative regulator of PD-L1, and zosuquidar may act as a potential immunotherapy agent by triggering PD-L1 degradation in the early secretory pathway., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Tacrolimus (Tc) is an immunosuppressant used in transplant patients, but its therapeutic range is narrow, making precise dosing essential. This study investigates the association of three single nucleotide polymorphisms (SNPs) (ABCB1 3435C>T, 1236C>T, 2677G>T/A) with Tc levels over time to gain better insights into their role in personalized medicine. We conducted the study over four distinct periods: 1-14 days, 15-30 days, 31-60 days, and beyond 60 days post-transplantation. The analysis included allele, genotype, haplotype, and diplotype frequencies of the three SNPs concerning Tc blood levels. Statistical significance was determined, and false discovery rate ( P ) correction was applied where appropriate. Significant associations were found between the C (ABCB1 C1236T), A alleles (ABCB1 G2677T/A), the CAC haplotype and lower Tc levels. The CAC-TGT and TGT-TGT diplotypes significantly influence how patients metabolize the drug. The TGT haplotype and the AA genotype (ABCB1 G2677T/A) were associated with higher Tc levels, suggesting a long-term genetic influence. Genetic factors, specifically certain SNPs and diplotypes, significantly impact Tc blood levels, with their influence varying over time.FDR ) correction was applied where appropriate. Significant associations were found between the C (ABCB1 C1236T), A alleles (ABCB1 G2677T/A), the CAC haplotype and lower Tc levels. The CAC-TGT and TGT-TGT diplotypes significantly influence how patients metabolize the drug. The TGT haplotype and the AA genotype (ABCB1 G2677T/A) were associated with higher Tc levels, suggesting a long-term genetic influence. Genetic factors, specifically certain SNPs and diplotypes, significantly impact Tc blood levels, with their influence varying over time.

Zotizalkib (TPX-0131), a fourth-generation macrocyclic anaplastic lymphoma kinase (ALK) inhibitor, is designed to overcome resistance due to secondary ALK mutations in non-small cell lung cancer (NSCLC). We here evaluated the pharmacokinetic roles of the ABCB1 (P-gp/MDR1) and ABCG2 (BCRP) efflux transporters, OATP1 influx transporters and the metabolizing enzymes CES1 and CYP3A in plasma and tissue disposition of zotizalkib after oral administration in relevant mouse models. Zotizalkib was efficiently transported by hABCB1 in vitro. In vivo, a significant ∼9-fold higher brain-to-plasma ratio was observed in Abcb1a/b -/- and Abcb1a/b;Abcg2 mice, suggesting that mAbcb1a/b markedly restricts the brain accumulation of zotizalkib. ABCB1-mediated efflux of zotizalkib was completely inhibited by elacridar, a dual ABCB1/ABCG2 inhibitor, increasing brain exposure without any signs of acute CNS-related toxicities. In -/- compared to wild-type mice. No change in brain disposition was observed in Abcg2 -/- mice, suggesting that mAbcb1a/b markedly restricts the brain accumulation of zotizalkib. ABCB1-mediated efflux of zotizalkib was completely inhibited by elacridar, a dual ABCB1/ABCG2 inhibitor, increasing brain exposure without any signs of acute CNS-related toxicities. In Oatp1a/b -/- mice, no marked changes in plasma exposure or tissue-to-plasma ratios were observed, indicating that zotizalkib is not a substantial in vivo substrate for mOatp1a/b. Zotizalkib may further be metabolized by CYP3A4 but only noticeably at low plasma concentrations. In Ces1 -/- mice, a 2.5-fold lower plasma exposure was seen compared to wild-type, without alterations in tissue distribution. This suggests increased plasma retention of zotizalkib by binding to the abundant mouse plasma Ces1c. Notably, the hepatic expression of human CES1 did not affect zotizalkib plasma exposure or tissue distribution. The obtained pharmacokinetic insights may be useful for the further development and optimization of therapeutic efficacy and safety of zotizalkib and related compact macrocyclic ALK inhibitors.

Everolimus is an oral mammalian target of rapamycin (mTOR) inhibitor used in cancer chemotherapy and transplantation. Due to its therapeutic properties, everolimus has been used long-term in clinical practice. Drug interactions with everolimus during gastrointestinal absorption can alter the oral bioavailability of everolimus and/or concomitant drugs. However, the effects of everolimus on gastrointestinal absorption remain unknown. The present study assessed the impact of continuous exposure to everolimus on expression and function of the ATP-binding cassette (ABC) transporter ABCB1 and ABCG2 using a Caco-2 intestinal cell model. Caco-2 subline, Caco/EV, was established by continuously exposing Caco-2 cells to 1 µM everolimus. Cell viability was evaluated using WST-1 assay. mRNA levels were measured by reverse transcription-quantitative PCR. Transport activity of ABCB1 was evaluated through the cellular accumulation of Rhodamin 123, a substrate for ABCB1. The half-maximal inhibitory concentration (IC 50 ) values for everolimus in Caco-2 and Caco/EV cells were 0.31 and 4.33 µM, respectively, indicating 14-fold resistance in Caco/EV cells. Sensitivity to paclitaxel and 7-ethyl-10-hydroxycamptothecin, which are substrates for ABCB1 and ABCG2, respectively, was enhanced in Caco/EV, but not in Caco-2 cells. The IC 50 values of cisplatin were comparable in both cell lines. Furthermore, mRNA expression levels of ABCB1 and ABCG2 were lower in Caco/EV cells than in Caco-2 cells, and the cellular accumulation of Rhodamine 123 was significantly higher in Caco/EV cells. These findings demonstrated that continuous exposure to everolimus suppressed the expression and function of ABCB1 and ABCG2, suggesting potential drug-drug interactions via the suppression of ABCB1 and ABCG2 in the intestinal tract., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Nakayama et al.)

Ovarian cancer (OC) is the deadliest gynecological malignancy, having a high mortality rate due to its asymptomatic nature, chemoresistance, and recurrence. However, the proper mechanistic knowledge behind these phenomena is still inadequate. Cancer recurrence is commonly observed due to cancer stem cells which also show chemoresistance. We aimed to decipher the molecular mechanism behind chemoresistance and stemness in OC. Earlier studies suggested that PITX2, a homeobox transcription factor and, its different isoforms are associated with OC progression upon regulating different signaling pathways. Moreover, they regulate the expression of drug efflux transporters in kidney and colon cancer, rendering chemoresistance properties in the tumor cell. Considering these backgrounds, we decided to look for the role of PITX2 isoforms in promoting stemness and chemoresistance in OC cells. In this study, PITX2A/B has been shown to promote stemness and to enhance the transcription of ABCB1. PITX2 has been discovered to augment ABCB1 gene expression by directly binding to its promoter. To further investigate the regulatory mechanism of PITX2 gene expression, we found that TGFβ signaling could augment the PITX2A/B expression through both SMAD and non-SMAD signaling pathways. Collectively, we conclude that TGFβ1-activated PITX2A/B induces stem-like features and chemoresistance properties in the OC cells., Competing Interests: The authors declare no conflicts of interests.

Objective: The main objective of the study is to explore the potential molecular benefits of Nab-paclitaxel as an effective advanced chemotherapeutic agent for HER2-positive breast cancer patients. Specifically, the study aims to assess Nab-paclitaxel as a potential drug candidate for breast cancer treatment., Methods: This study used bioinformatics and cheminformatics to analyze the HER2 signaling pathway and its possible interactions with Nab-Paclitaxel. This involves using pharmacokinetic profiling software to evaluate its physicochemical properties, analyzing its potential impact on gene expression modulation, and assessing its binding affinity to the HER2 receptor through molecular docking., Result: The results indicate that the most favorable docking pose occurs between chain B of the HER-2 receptor and Paclitaxel, with a binding energy of -9.4 kcal/mol. Notably, a hydrogen bond is observed in ARG849, with 3.0 Angstrom (Å). Previous research highlights Paclitaxel's impact on breast cancer patients' genes, particularly the ABCB1 gene responsible for P-glycoprotein production, contributing to drug resistance in chemotherapy. Nab-paclitaxel exhibits potential ease of metabolism, as it minimally inhibits drug-metabolizing cytochrome P450 enzymes. Additionally, despite initial concerns related to drug-likeness parameters and molecular weight discrepancies, the pharmacokinetic profile of Nab-Paclitaxel suggests improvements in delivery facilitated by an albumin-supported nanoparticle delivery mechanism., Conclusion: The binding energy confirms the secure docking of ligands to receptors, suggesting the stability of the interaction between them. Nevertheless, prolonged administration of Paclitaxel poses the risk of inducing drug resistance, a significant factor contributing to treatment failure. This emphasizes the need to explore new candidate drug combinations or identify alternative drug-binding interaction sites. Such endeavors hold the potential to enhance the effectiveness of drug treatments and address challenges associated with prolonged Paclitaxel use.

Background: Cholangiocarcinoma (CCA) is a highly malignant, rapidly progressing tumor of the bile duct. Owing to its chemoresistance, it always has an extremely poor prognosis. Therefore, detailed elucidation of the mechanisms of chemoresistance and identification of therapeutic targets are still needed., Methods: We analyzed the expression of MBD2 (Methyl-CpG-binding domain 2) in CCA and normal bile duct tissues using the public database and immunohistochemistry (IHC). The roles of MBD2 in CCA cell proliferation, migration, and chemoresistance ability were validated through CCK-8, plate cloning assay, wound healing assays and xenograft mouse model. In addition, we constructed a primary CCA mouse model to further confirm the effect of MBD2. RNA-seq and co-IP-MS were used to identify the mechanisms by how MBD2 leads to chemoresistance., Results: MBD2 was upregulated in CCA. It promoted the proliferation, migration and chemoresistance of CCA cells. Mechanistically, MBD2 directly interacted with WDR5, bound to the promoter of ABCB1, promoted the trimethylation of H3K4 in this region through KMT2A, and activated the expression of ABCB1. Knocking down WDR5 or KMT2A blocked the transcriptional activation of ABCB1 by MBD2. The molecular inhibitor MM-102 targeted the interaction of WDR5 with KMT2A. MM-102 inhibited the expression of ABCB1 in CCA cells and decreased the chemoresistance of CCA to cisplatin., Conclusion: MBD2 promotes the progression and chemoresistance of CCA through interactions with WDR5. MM-102 can effectively block this process and increase the sensitivity of CCA to cisplatin., (© 2024. The Author(s).)

Drug transporters play a pivotal role in modulating drug disposition and are subject to alterations under inflammatory conditions. This study aimed to elucidate the intricate expression patterns of drug transporters during both acute and chronic inflammation, which are closely linked to malignant transformation. To investigate acute inflammation, we employed an in vitro model by subjecting Caco-2 cells to various inflammatory stimuli (IL-1β, TNF-α, or LPS) individually or in combination. The successful induction of inflammation was confirmed by robust increases in IL-6 and NO production. Notably, inflamed Caco-2 cells exhibited significantly diminished levels of ABCB1 and ABCG2, while the expression of ABCC2 was upregulated. For chronic inflammation induction in vivo, we employed the well-established AOM/DSS mouse model known for its association with colitis-driven tumorigenesis. Persistent inflammation was effectively monitored throughout the experiment via elevated IL-6 and NO levels. The sequential stages of tumorigenesis were confirmed through Ki-67 immunohistochemistry. Intriguingly, we observed gradual alterations in the expression patterns of the studied drug transporters during stepwise induction, with ABCB1, ABCG2, and ABCC1 showing downregulation and ABCC2 exhibiting upregulation. Immunohistochemistry further revealed dynamic changes in the expression of ABCB1 and ABCC2 during the induction cycles, closely paralleling the gradual increase in Ki-67 expression observed during the development of precancerous lesions. Collectively, our findings underscore the significant impact of inflammation on drug transporter expression, potentially influencing the process of malignant transformation of the colon., (© 2024 Wiley Periodicals LLC.)

Background: Gallbladder cancer (GBC) is a biologically aggressive malignancy requiring appropriate biomarkers to improve its outcome. Role of ABC transporters (ABCB1 and ABCG2) has been linked to cancer aggressiveness, tumorigenesis and multidrug resistance. Herein, we studied the prognostic implication of ABCB1 and ABCG2 in GBC., Methods: Fresh tissue (tumour & normal) samples collected from 54 patients who underwent R0 resection, were analysed for mRNA and protein expression of ABCB1 and ABCG2 by quantitative Real-Time PCR and western blotting, respectively, in this prospective study. The molecular findings were correlated with clinical-pathological parameters using χ2 and fisher exact test. The molecular changes in ABCB1 and ABCG2 were analysed for predicting overall survival (OS), disease-free survival (DFS) and response to chemotherapy using Kaplan-Meier log-rank test and Cox regression multivariate analysis., Results: The mean age of the cohort was 50 ± 13.2 with 26 (48.1%) in patients having early stage gallbladder cancer (GBC). Over-expression of ABCB1 and ABCG2 was noted in 32/54 (59%) and 40/54 (74%) cases, respectively. The protein expression of ABCB1(P-glycoprotein) and ABCG2 (BCRP) was higher in 27/54 (50%) and 37/54 (59%) cases, respectively. The mean OS and DFS was 20.7 ± 11.5 and 19.3 ± 12.2 months at median follow-up of 24 months. The TNM stage, lymph node metastasis, and presence of gallstone were significant factors for predicting OS and DFS on multivariate analysis. Both ABCB1 and ABCG2 did not show any significant correlation with OS and DFS with similar incidences of late death and recurrence among over-expression and down-expression. Sub-group comparison suggests that change in expression pattern of ABCB1 and ABCG2 may not affect response to chemotherapy in GBC., Conclusion: Altered expression of ABCB1 and ABCG2 may not be a useful prognostic marker for survival or response to chemotherapy in GBC. Presently, histo-pathological characteristics and associated gallstones are the important predictors for survival and recurrence in GBC., (© 2024 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Aims: Despite aggressive treatment, the recurrence of glioma is an inevitable occurrence, leading to unsatisfactory clinical outcomes. A plausible explanation for this phenomenon is the phenotypic alterations that glioma cells undergo aggressive therapies, such as TMZ-therapy. However, the underlying mechanisms behind these changes are not well understood., Methods: The TMZ chemotherapy resistance model was employed to assess the expression of intercellular adhesion molecule-1 (ICAM1) in both in vitro and in vivo settings. The potential role of ICAM1 in regulating TMZ chemotherapy resistance was investigated through knockout and overexpression techniques. Furthermore, the mechanism underlying ICAM1-mediated TMZ chemotherapy resistance was examined using diverse molecular biological methods, and the lipid raft protein was subsequently isolated to investigate the cellular subcomponents where ICAM1 operates., Results: Acquired TMZ resistant (TMZ-R) glioma models heightened production of intercellular adhesion molecule-1 (ICAM1) in TMZ-R glioma cells. Additionally, we observed a significant suppression of TMZ-R glioma proliferation upon inhibition of ICAM1, which was attributed to the enhanced intracellular accumulation of TMZ. Our findings provide evidence supporting the role of ICAM1, a proinflammatory marker, in promoting the expression of ABCB1 on the cell membrane of TMZ-resistant cells. We have elucidated the mechanistic pathway by which ICAM1 modulates phosphorylated moesin, leading to an increase in ABCB1 expression on the membrane. Furthermore, our research has revealed that the regulation of moesin by ICAM1 was instrumental in facilitating the assembly of ABCB1 exclusively on the lipid raft of the membrane., Conclusions: Our findings suggest that ICAM1 is an important mediator in TMZ-resistant gliomas and targeting ICAM1 may provide a new strategy for enhancing the efficacy of TMZ therapy against glioma., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rong Hu reports administrative support, article publishing charges, equipment, drugs, or supplies, statistical analysis, and writing assistance were provided by National Natural Science Foundation of China. Qing Wang reports administrative support, article publishing charges, equipment, drugs, or supplies, statistical analysis, travel, and writing assistance were provided by Natural Science Foundation of Jiangsu Province., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Human P-glycoprotein (P-gp) utilizes energy from ATP hydrolysis for the efflux of chemically dissimilar amphipathic small molecules and plays an important role in the development of resistance to chemotherapeutic agents in most cancers. Efforts to overcome drug resistance have focused on inhibiting P-gp-mediated drug efflux. Understanding the features distinguishing P-gp inhibitors from substrates is critical. Cryo-electron microscopy has revealed distinct binding patterns, emphasizing the role of the L-site or access tunnel in inhibition. We substituted 5-9 residues of the L-site with alanine to investigate whether the binding of a second inhibitor molecule to the L-site is required for inhibiting drug efflux. We reveal, for the first time, that mutations in the L-site affect the drug efflux activity of P-gp, despite their distance from the substrate-binding pocket (SBP). Surprisingly, after the mutations were introduced, inhibitors such as tariquidar and zosuquidar still inhibited drug efflux by mutant P-gps. Communication between the transmembrane helices (TMHs) and nucleotide-binding domains (NBDs) was evaluated using the ATPase assay, revealing distinct modulation patterns by inhibitors for the mutants, with zosuquidar exhibiting substrate-like stimulation of ATPase. Furthermore, L-site mutations abolished ATP-dependent thermal stabilization. In silico molecular docking studies corroborated the altered inhibitor binding due to mutations in the L-site residues, shedding light on their critical role in substrate transport and inhibitor interactions with P-gp. These findings suggest that inhibitors bind either to the SBP alone, and/or to alternate site(s) when the L-site is disabled by mutagenesis., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

Bitter taste receptors (TAS2Rs) are not only expressed in the oral cavity but also in skin. Extraoral TAS2Rs are thought to be involved in non-taste perception and tissue-specific functions. Keratinocytes that express TAS2Rs in the skin provide a first-line defense against external threats. However, the functional roles of these receptors in host defense remain unclear. Here, we demonstrated the sensory role of intracellularly located TAS2Rs against toxic substances in keratinocytes. Although many G protein-coupled receptors elicit signals from the surface, TAS2Rs were found to localize intracellularly, possibly to the ER, in human keratinocytes and HaCaT cells. TAS2R38, one of the TAS2R members, activated the G α12/13 /RhoA/ROCK/p38 MAP kinase/NF-κB pathway upon stimulation by phenylthiocarbamide (PTC), an agonist for this receptor, leading to the production of ABC transporters, such as ABCB1, in these cells. Notably, treatment with bitter compounds, such as PTC and saccharin, induced the upregulation of ABCB1 in HaCaT cells. Mechanistically, intracellular TAS2R38 and its downstream signaling G α12/13 /RhoA/ROCK/p38 MAP kinase/NF-κB pathway were identified to be responsible for the above effect. Pretreatment with PTC prevented the accumulation of rhodamine 123 because of its excretion via ABCB1. Furthermore, pretreatment with PTC or saccharin counteracted the effect of the toxic compound, diphenhydramine, and pretreated HaCaT cells were found to proliferate faster than untreated cells. This anti-toxic effect was suppressed by treatment with verapamil, an ABCB1 inhibitor, indicating that enhanced ABCB1 helps clear toxic substances. Altogether, harmless activators of TAS2Rs may be promising drugs that enhance the excretion of toxic substances from the human skin., (©2024 The Authors FASEB BioAdvances published by The Federation of American Societies for Experimental Biology.)

Gefitinib is a selective inhibitor of the epidermal growth factor receptor that is used to treat advanced and metastatic non-small cell lung cancer (NSCLC). Dermatological adverse reactions are most commonly associated with gefitinib treatment. The cause of adverse reactions in individuals is multifactorial. Pharmacogenetics is an effective tool to detect such adverse reactions. This case report describes a female patient with NSCLC who was administered gefitinib at a dose of 250 mg/day. However, due to severe adverse dermatological reactions, the treatment was interrupted for 15 d and antibiotic therapy was administered to manage the skin rashes, maculopapular rashes, and hyperpigmentation. Treatment adherence was adequate, and no drug interactions were detected. A pharmacogenetic analysis revealed homozygosity in the ATP-binding cassette (ABC)-B1 rs1128503 (c.1236A>G), heterozygosity in ABCG2 rs2231142 (c.421G>T) and rs2622604 (c.-20+614T>C), and a non-functional variant of the cytochrome P450 family 3, subfamily A, member 5 ( CYP3A5 ). The relationship between altered genetic variants and the presence of adverse reactions induced by gefitinib is still controversial. Overall, this case report highlights the importance of continuing to study pharmacogenetics as predictors of adverse drug reactions.

Background: Pharmacotherapy for brain diseases is severely compromised by the blood-brain barrier (BBB). ABCB1 and ABCG2 are drug transporters that restrict drug entry into the brain and their inhibition can be used as a strategy to boost drug delivery and pharmacotherapy for brain diseases., Methods: We employed elacridar and tariquidar in mice to explore the conditions for effective inhibition at the BBB. Abcg2;Abcb1a/b knockout (KO), Abcb1a/b KO, Abcg2 KO and wild-type (WT) mice received a 3 h i.p. infusion of a cocktail of 8 typical substrate drugs in combination with elacridar or tariquidar at a range of doses. Abcg2;Abcb1a/b KO mice were used as the reference for complete inhibition, while single KO mice were used to assess the potency to inhibit the remaining transporter. Brain and plasma drug levels were measured by LC-MS/MS., Results: Complete inhibition of ABCB1 at the BBB is achieved when the elacridar plasma level reaches 1200 nM, whereas tariquidar requires at least 4000 nM. Inhibition of ABCG2 is more difficult. Elacridar inhibits ABCG2-mediated efflux of weak but not strong ABCG2 substrates. Strikingly, tariquidar does not enhance the brain uptake of any ABCG2-subtrate drug. Similarly, elacridar, but not tariquidar, was able to inhibit its own brain efflux in ABCG2-proficient mice. The plasma protein binding of elacridar and tariquidar was very high but similar in mouse and human plasma, facilitating the translation of mouse data to humans., Conclusions: This work shows that elacridar is an effective pharmacokinetic-enhancer for the brain delivery of ABCB1 and weaker ABCG2 substrate drugs when a plasma concentration of 1200 nM is exceeded., (© 2024. The Author(s).)

Background: In lung transplant patients, direct oral anticoagulants are often taken in combination with immunosuppressive drugs such as tacrolimus. Since tacrolimus is a substrate and inhibitor of the efflux protein ABCB1, also transporting direct oral anticoagulants, a possible drug-drug interaction mediated by competition for this transporter needs to be investigated., Objectives: To determine the in vitro effect of tacrolimus on ABCB1-mediated rivaroxaban transport in order to support clinician practice., Methods: Recombinant cell line models, based on human embryonic kidney 293 cells, were generated by a stable transfection process to overexpress ABCB1 or not (control cells). The impact of tacrolimus on ABCB1-mediated rivaroxaban transport was assessed by accumulation experiments., Results: ABCB1 expression decreased the cellular accumulation of rivaroxaban and tacrolimus at their respective clinically relevant concentrations when compared with control cells. This confirms the involvement of ABCB1 in the active transport of tacrolimus and rivaroxaban. However, tacrolimus had no significant influence on rivaroxaban disposition at those clinically relevant concentrations., Conclusion: Our study does not provide evidence for a possible interaction between tacrolimus and rivaroxaban when used together in practice., (© 2024 The Authors.)

Paclitaxel is commonly used to treat breast, ovarian, lung, esophageal, gastric, pancreatic cancer, and neck cancer cells. Cancer recurrence is observed in patients treated with paclitaxel due to paclitaxel resistance emergence. Resistant mechanisms are observed in cancer cells treated with paclitaxel, docetaxel, and cabazitaxel including changes in the target molecule β-tubulin of mitosis, molecular mechanisms that activate efflux drug out of the cells, and alterations in regulatory proteins of apoptosis. This review discusses new molecular mechanisms of taxane resistance, such as overexpression of genes like the multidrug resistance genes and EDIL3, ABCB1, MRP1, and TRAG-3/CSAG2 genes. Moreover, significant lncRNAs are detected in paclitaxel resistance, such as lncRNA H19 and cross-resistance between taxanes. This review contributed to discovering new treatment strategies for taxane resistance and increasing the responsiveness of cancer cells toward chemotherapeutic drugs., (© 2024. The Author(s).)

The association between polymorphisms of the human ATP binding cassette subfamily B member 1 (ABCB1) gene and opioid response has attracted intense attention recently. As the ABCB1 gene encodes for the transporter P-glycoprotein in the brain and intestine involved in the pharmacokinetics of opioids, we investigated the effects of ABCB1 genetic polymorphisms on doses of opioids for pain relief and determined which pharmacokinetic process was affected in cancer pain patients. Sixty-eight cancer pain patients admitted for intrathecal therapy (ITT) were included. The association between ABCB1 genetic polymorphisms (C3435T, C1236T, G2677T/A and A61G) and systemic doses of opioids before ITT were investigated. Concentrations of oxycodone in plasma and cerebrospinal fluid (CSF) were determined by HPLC-MS/MS in 17 patients treated with oral oxycodone before ITT, and the influences of ABCB1 genetic polymorphisms on plasma-concentration to oral-dose ratios and CSF-concentration to plasma-concentration ratios of oral oxycodone were further analyzed. ABCB1 C3435T and G2677T/A polymorphisms were significantly associated with systemic doses of opioids before ITT, which coincided with the influences of ABCB1 C3435T and G2677T/A polymorphisms on the ratios of plasma-concentration to oral-dose. However, no significant difference was found in ratios of CSF-concentration to plasma-concentration among ABCB1 SNP genotypes. The present study provided the first evidence that ABCB1 C3435T and G2677T/A polymorphisms affect opioid requirement in cancer pain patients via altering transportation function of P-glycoprotein in the intestine, which will further expand our knowledge about pharmacokinetics of opioids and could contribute to the individualization of opioids use., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background/aim: Everolimus-resistant Caki/EV and 786/EV cells have been established from human derived renal cell carcinoma cells, Caki-2 and 786-O, respectively. These cells exhibit resistance to everolimus and to other mTOR inhibitors and erlotinib. However, the sensitivity of these resistant cells to classical and cytotoxic anticancer drugs remain unclear. The aim of the study was to examine sensitivity of Caki/EV and 786/EV cells to classical and cytotoxic anticancer drugs., Materials and Methods: Sensitivity to classical and cytotoxic anticancer drugs in Caki/EV and 786/EV cells was evaluated using the WST-1 (tetrazolium salts) colorimetric assay and was compared to those of the corresponding parental cells. The mRNA expression levels were measured using SYBR ® green based quantitative reverse transcription-polymerase chain reaction., Results: Sensitivity to vinblastine, vincristine, paclitaxel, doxorubicin, etoposide, SN-38 (active metabolite of irinotecan), 5-fluorouracil, cisplatin, and carboplatin varied in the resistant cells. Sensitivity to carboplatin and SN-38 was comparable between resistant cells and their parental cells, whereas sensitivity to vinca alkaloids, etoposide, 5-fluorouracil, and cisplatin decreased in the resistant cells. However, sensitivity to paclitaxel and doxorubicin was remarkably enhanced in both resistant cells compared to that of parental cells, this could be partially explained by down-regulation of ABCB1 mRNA expression., Conclusion: The everolimus-resistant Caki/EV and 786/EV cells showed cross-resistance to classical and cytotoxic anticancer drugs. However, Caki/EV and 786/EV cells exhibited a remarkable increase in sensitivity to paclitaxel and doxorubicin, and ABCB1 mRNA was down-regulated in response to long-term exposure to everolimus., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Docetaxel (Doc) currently serves as the primary first-line treatment for patients with castrate-resistant prostate cancer (CRPC). Erastin, a small molecule compound, can trigger inhibition of the cystine-glutamate reverse transport system and other pathways, leading to iron-dependent cell death (ferroptosis). Beyond its role in inducing cancer cell death, erastin demonstrates potential when combined with chemotherapy drugs to heighten cancer cell drug susceptibility. However, the augmentation by erastin of the effects of Doc treatment on prostate cancer, and the underlying mechanisms involved, remain unclear. In the present study, we determined the role and the underlying molecular mechanism of erastin against CRPC. The results showed that CRPC cell lines were resistant to Doc, and the expression of ferroptosis-related factors in drug-resistant cell lines was downregulated. Erastin, in synergy with Doc, exerts a pro-apoptotic effect. Erastin significantly inhibited the activity of ATP-binding cassette subfamily B member 1 (ABCB1) but did not change its protein expression and localization. Finally, in mice, erastin treatment dramatically reduced tumor growth in vivo. Taken together, our findings demonstrate that erastin enhances Doc-induced apoptosis to a certain extent and reverses Doc resistance in prostate cancer by inhibiting the activity of multidrug-resistant protein ABCB1., (© 2024 Federation of European Biochemical Societies.)

Background: Clopidogrel has been the primary choice of antiplatelet in ischemic stroke that inhibits adenosine diphosphate (ADP)-induced platelet aggregation. P-glycoprotein (P-gp) multidrug resistance-1 (MDR1) is a transmembrane efflux transporter in intestinal cells that plays a significant role in clopidogrel absorption, therefore may affect platelet aggregation. P-gp is encoded by the ABCB1 gene. This study aims to evaluate the effect of ABCB1 polymorphism on clopidogrel response variability in ischemic stroke patients and its genotype frequency., Methods: A cross-sectional study was conducted in ischemic stroke patients who received clopidogrel between 2020 and 2023 in RSUI/RSCM. All subjects were assessed for ABCB1 polymorphisms C3435T and C1236T. Platelet aggregation were measured using VerifyNow PRU. Clopidogrel response variability was classified into unresponsive (> 208 PRU), responsive (95-208 PRU), and bleeding risk (< 95 PRU)., Results: 124 subjects enrolled in this study, with 12,9% of subjects classified as non-responsive/resistant, 49,5% as responsive, and 41,9% as bleeding risk. ABCB1 C1236T homozygote wildtype (CC) was associated with 3,76 times higher bleeding risk than other variants (p = 0,008; 95%CI 1,41 - 10,07). Genotype frequency of ABCB1 C3435T homozygote wildtype, heterozygote, and homozygote variants were 35,9%, 43,5% and 16,9%, respectively; while the genotype frequency of ABCB1 C1236T were 17,8%, 39,5%, and 42,7%, respectively., Conclusion: ABCB1 C1236T homozygote wildtype was associated with 3,76 times higher bleeding risk than other variants. The most common genotype frequency of ABCB1 C1236T was homozygote variant; while for ABCB1 C3435T was heterozygote., (© 2024. The Author(s).)

P-glycoprotein (P-gp) plays a crucial role in cellular detoxification and drug efflux processes, transitioning between inward-facing (IF) open, occluded, and outward-facing (OF) states to facilitate substrate transport. Its role is critical in cancer therapy, where P-gp contributes to the multidrug resistance phenotype. In our study, classical and enhanced molecular dynamics (MD) simulations were conducted to dissect the structural and functional features of the P-gp conformational states. Our advanced MD simulations, including kinetically excited targeted MD (ketMD) and adiabatic biasing MD (ABMD), provided deeper insights into state transition and translocation mechanisms. Our findings suggest that the unkinking of TM4 and TM10 helices is a prerequisite for correctly achieving the outward conformation. Simulations of the IF-occluded conformations, characterized by kinked TM4 and TM10 helices, consistently demonstrated altered communication between the transmembrane domains (TMDs) and nucleotide binding domain 2 (NBD2), suggesting the implication of this interface in inhibiting P-gp's efflux function. A particular emphasis was placed on the unstructured linker segment connecting the NBD1 to TMD2 and its role in the transporter's dynamics. With the linker present, we specifically noticed a potential entrance of cholesterol (CHOL) through the TM4-TM6 portal, shedding light on crucial residues involved in accommodating CHOL. We therefore suggest that this entry mechanism could be employed for some P-gp substrates or inhibitors. Our results provide critical data for understanding P-gp functioning and developing new P-gp inhibitors for establishing more effective strategies against multidrug resistance., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors.)

Opnurasib (JDQ443) is a newly developed oral KRAS G12C inhibitor, with a binding mechanism distinct from the registered KRAS G12C inhibitors sotorasib and adagrasib. Phase I and II clinical trials for opnurasib in NSCLC are ongoing. We evaluated the pharmacokinetic roles of the ABCB1 (P-gp/MDR1) and ABCG2 (BCRP) efflux and OATP1 influx transporters, and of the metabolizing enzymes CYP3A and CES1 in plasma and tissue disposition of oral opnurasib, using genetically modified cell lines and mouse models. In vitro, opnurasib was potently transported by human (h)ABCB1 and slightly by mouse (m)Abcg2. In Abcb1a/b- and Abcb1a/b;Abcg2-deficient mice, a significant ∼100-fold increase in brain-to-plasma ratios was observed. Brain penetration was unchanged in Abcg2 -/- mice. ABCB1 activity in the blood-brain barrier may therefore potentially limit the efficacy of opnurasib against brain metastases. The Abcb1a/b transporter activity could be almost completely reversed by co-administration of elacridar, a dual ABCB1/ABCG2 inhibitor, increasing the brain penetration without any behavioral or postural signs of acute CNS-related toxicity. No significant pharmacokinetic roles of the OATP1 transporters were observed. Transgenic human CYP3A4 did not substantially affect the plasma exposure of opnurasib, indicating that opnurasib is likely not a sensitive CYP3A4 substrate. Interestingly, Ces1 -/- mice showed a 4-fold lower opnurasib plasma exposure compared to wild-type mice, whereas no strong effect was seen on the tissue distribution. Plasma Ces1c therefore likely binds opnurasib, increasing its retention in plasma. The obtained pharmacokinetic insights may be useful for further optimization of the clinical efficacy and safety of opnurasib, and might reveal potential drug-drug interaction risks., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Allelic variants of genes encoding enzymes of the esterase system ( CES1 ) and P-glycoprotein ( ABCB1 ) can change the metabolism and pharmacokinetics of dabigatran. Therefore, they act as determining factors in the development of side effects, especially bleeding. We analyzed the genotype-phenotype relationship of ABCB1 (rs1045642, rs4148738, rs2032582, and rs1128503) and CES1 (rs8192935, rs71647871, and rs2244613) polymorphisms in patients with atrial fibrillation who had been treated with dabigatran., Methods: A total of 150 patients were recruited for this study. TaqMan technology was used for SNP genotyping., Results: Patients with the rs2244613 GG genotype had a lower concentration (55.27 ± 34.22 ng/ml) compared to those with the TT genotype (63.33 ± 52.25 ng/ml) (additive model, P = 0.000). Individuals with the rs8192935 AA genotype had a lower concentration (52.72 ± 30.45 ng/ml) compared to those with the GG genotype (79.78 ± 57 ng/ml) (additive model, P = 0.001). The APTT values among the different genotypes of the ABCB1 SNPs, rs4148738 and rs1045642, were significantly different (P = 0.035 and P = 0.024, respectively)., Conclusion: Our research demonstrates that the CES1 polymorphisms, rs8192935 and rs2244613, are associated with the pharmacodynamics and pharmacokinetics of dabigatran in the Kazakh subpopulation., Competing Interests: The authors declare no conflict of interest., (© The Author(s).)

The CLEFF4 sub clone from stock late passage Caco2 cells has a unique property of being able to develop polarised cell monolayers with high P-gp expression and tight junctions much quicker than the original cell line. Instead of being useful for transport studies 21-24 days after initiating culture, the CLEFF4 cell line matures in 5-6 days with tight junctions surpassing that of 3 week old Caco2 cells in that time frame [1]. This has enabled the CLEFF4 cell line to provide measures of apparent permeability for potential drug candidates, so important for pre-clinical drug development, 4 times faster than the original cell line. RNA samples were collected and analysed at days 4 and 7 of culture over a 3 year period and had full RNA transcriptome analysed by the ranaseq.eu open bioinformatics platform. Protein was also collected from day 4 to day 22 of culture. Differential expression data from the FASTQ files have shown significant differences in expression in multiple genes involved with drug efflux, tight junctions, phase 2 metabolism and growth factors, which have been confirmed from protein determination that may hold the key to understanding accelerated human cell maturation. These gene expression results may be significant for other tissues beyond the gastrointestinal tract, and potentially for accelerated cell growth for the new field of laboratory grown tissues for organ replacement. The data also confirms the different genetic expression in CLEFF4 cells compared to Caco2 and the stable nature of the different expression over many years., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Hepatotoxicity has emerged as a major cause of statin treatment interruption. Although organic anion-transporting polypeptide 1B1 (SLCO1B1), multidrug resistance protein 1 (ABCB1), and breast cancer resistance protein (ABCG2) have been identified as transporters of statins, knowledge of their role in statin-associated hepatotoxicity remains limited. Therefore, we aimed to conduct a comprehensive analysis to elucidate the association between hepatotoxicity and SLCO1B1, ABCB1, and ABCG2 polymorphisms., Methods: This study retrospectively analyzed prospectively collected samples. We selected 10 single nucleotide polymorphisms (SNPs) of SLCO1B1, 9 SNPs of ABCB1, and 12 SNPs of ABCG2. We developed two models for multivariable analyses (Model I: clinical factors only; Model II: both clinical and genetic factors), and the attributable risk (%) of variables in Model II was determined., Results: Among 851 patients, 66 (7.8%) developed hepatotoxicity. In Model I, lipophilic statins, atrial fibrillation (Afib), and diabetes mellitus showed a significant association with hepatotoxicity. In Model II, lipophilic statins and Afib, SLCO1B1 rs11045818 A allele, SLCO1B1 rs4149035 T allele, and ABCG2 rs2622629 TT genotype were associated with higher hepatotoxicity risk. Among them, the SLCO1B1 rs11045818 A allele exhibited the highest attributable risk (93.2%). The area under the receiver operating characteristic curve in Model I was 0.62 (95% CI: 0.55-0.69), and it was increased to 0.71 in Model II (95% CI: 0.64-0.77)., Conclusion: This study investigated the correlation between hepatotoxicity and polymorphisms of transporter genes in patients taking statins. The findings could help improve personalized treatments for patients receiving statin therapy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The impact of tyrosine kinase inhibitors (TKIs) on multidrug resistance (MDR) in non-small cell lung carcinoma (NSCLC) is a critical aspect of cancer therapy. While TKIs effectively target specific signaling pathways of cancer cells, they can also act as substrates for ABC transporters, potentially triggering MDR. The aim of our study was to evaluate the response of 17 patient-derived NSCLC cultures to 10 commonly prescribed TKIs and to correlate these responses with patient mutational profiles. Using an ex vivo immunofluorescence assay, we analyzed the expression of the MDR markers ABCB1, ABCC1, and ABCG2, and correlated these data with the genetic profiles of patients for a functional diagnostic approach. NSCLC cultures responded differently to TKIs, with erlotinib showing good efficacy regardless of mutation burden or EGFR status. However, the modulation of MDR mechanisms by erlotinib, such as increased ABCG2 expression, highlights the challenges associated with erlotinib treatment. Other TKIs showed limited efficacy, highlighting the variability of response in NSCLC. Genetic alterations in signaling pathways associated with drug resistance and sensitivity, including TP53 mutations, likely contributed to the variable responses to TKIs. The relationships between ABC transporter expression, gene alterations, and response to TKIs did not show consistent patterns. Our results suggest that in addition to mutational status, performing functional sensitivity screening is critical for identifying appropriate treatment strategies with TKIs. These results underscore the importance of considering drug sensitivity, off-target effects, MDR risks, and patient-specific genetic profiles when optimizing NSCLC treatment and highlight the potential for personalized approaches, especially in early stages.

P-glycoprotein (P-GP) is a transporter molecule expressed on the apical surface of capillary endothelial cells of the Blood-Brain Barrier (BBB), whose activity heavily influences drug distribution, including antidepressants. This transporter is encoded by ABCB1 gene, and genetic variations within ABCB1 gene have been proposed to affect drug efflux and have been previously associated with depression. In this context, we aimed to evaluate the role of C1236T , G2677TA and C3435T ABCB1 genetic polymorphisms in antidepressant treatment phenotypes from a cohort of patients harboring Major Depressive Disorder. Patients enrolled in the study consisted of 80 individuals with Major Depressive Disorder, who took part in a 27-month follow-up study at HML, Portugal. To investigate the correlation between ABCB1 polymorphisms and antidepressant response phenotypes, DNA was extracted from peripheral blood, and C1236T , C3435T and G2677TA polymorphisms were genotyped with TaqMan ® SNP Genotyping Assays. Despite the fact that the evaluated polymorphisms ( C1236T , C3435T and G2677TA ) were not associated with treatment resistant depression, or relapse, we observed that patients carrying TT genotype of the C3435T polymorphism remit earlier than the ones carrying CC or CT genotypes (10.2 weeks vs. 14.9 and 21.3, respectively, p = 0.028, Log-rank test). Since we found an association with C3435T and time to remission, and not to the absence of remission, we suggest that this polymorphism could have an impact on antidepressant drug distribution, and thus influence on the time to remission will occur, without influencing the risk of remission itself.

This systematic review and meta-analysis aimed to verify the association between the genetic variants of adenosine triphosphate (ATP)-binding cassette subfamily B member 1 ( ABCB1 ) and ATP-binding cassette subfamily G member 2 ( ABCG2 ) genes and the presence and severity of gefitinib-associated adverse reactions. We systematically searched PubMed, Virtual Health Library/Bireme, Scopus, Embase, and Web of Science databases for relevant studies published up to February 2024. In total, five studies were included in the review. Additionally, eight genetic variants related to ABCB1 (rs1045642, rs1128503, rs2032582, and rs1025836) and ABCG2 (rs2231142, rs2231137, rs2622604, and 15622C>T) genes were analyzed. Meta-analysis showed a significant association between the ABCB1 gene rs1045642 TT genotype and presence of diarrhea (OR = 5.41, 95% CI: 1.38-21.14, I 2 = 0%), the ABCB1 gene rs1128503 TT genotype and CT + TT group and the presence of skin rash (OR = 4.37, 95% CI: 1.51-12.61, I 2 = 0% and OR = 6.99, 95%CI: 1.61-30.30, I 2 = 0%, respectively), and the ABCG2 gene rs2231142 CC genotype and presence of diarrhea (OR = 3.87, 95% CI: 1.53-9.84, I 2 = 39%). No ABCB1 or ABCG2 genes were positively associated with the severity of adverse reactions associated with gefitinib. In conclusion, this study showed that ABCB1 and ABCG2 variants are likely to exhibit clinical implications in predicting the presence of adverse reactions to gefitinib.

Commensal enteric bacteria have evolved systems that enable growth in the ecologic niche of the host gastrointestinal tract. Animals evolved parallel mechanisms to survive the constant exposure to bacteria and their metabolic by-products. We propose that drug transporters encompass a crucial system to managing the gut microbiome. Drug transporters are present in the apical surface of gut epithelia. They detoxify cells from small molecules and toxins (xenobiotics) in the lumen. Here, we review what is known about commensal structure in the absence of the transporter ABCB1/P-glycoprotein in mammalian models. Knockout or low-activity alleles of ABCB1 lead to dysbiosis, Crohn's disease and ulcerative colitis in mammals. However, the exact function of ABCB1 in these contexts remain unclear. We highlight emerging models-the zebrafish Danio rerio and sea urchin Lytechinus pictus -that are poised to help dissect the fundamental mechanisms of ATP-binding cassette (ABC) transporters in the tolerance of commensal and pathogenic communities in the gut. We and others hypothesize that ABCB1 plays a direct role in exporting inflammatory bacterial products from host epithelia. Interdisciplinary work in this research area will lend novel insight to the transporter-mediated pathways that impact microbiome community structure and accelerate the pathogenesis of inflammatory bowel disease when perturbed. This article is part of the theme issue 'Sculpting the microbiome: how host factors determine and respond to microbial colonization'.

Paclitaxel resistance is associated with a poor prognosis in non-small cell lung cancer (NSCLC) patients, and currently, there is no promising drug for paclitaxel resistance. In this study, we investigated the molecular mechanisms underlying the chemoresistance in human NSCLC-derived cell lines. We constructed paclitaxel-resistant NSCLC cell lines (A549/PR and H460/PR) by long-term exposure to paclitaxel. We found that triptolide, a diterpenoid epoxide isolated from the Chinese medicinal herb Tripterygium wilfordii Hook F, effectively enhanced the sensitivity of paclitaxel-resistant cells to paclitaxel by reducing ABCB1 expression in vivo and in vitro. Through high-throughput sequencing, we identified the SHH-initiated Hedgehog signaling pathway playing an important role in this process. We demonstrated that triptolide directly bound to HNF1A, one of the transcription factors of SHH, and inhibited HNF1A/SHH expression, ensuing in attenuation of Hedgehog signaling. In NSCLC tumor tissue microarrays and cancer network databases, we found a positive correlation between HNF1A and SHH expression. Our results illuminate a novel molecular mechanism through which triptolide targets and inhibits HNF1A, thereby impeding the activation of the Hedgehog signaling pathway and reducing the expression of ABCB1. This study suggests the potential clinical application of triptolide and provides promising prospects in targeting the HNF1A/SHH pathway as a therapeutic strategy for NSCLC patients with paclitaxel resistance. Schematic diagram showing that triptolide overcomes paclitaxel resistance by mediating inhibition of the HNF1A/SHH/ABCB1 axis., (© 2024. The Author(s).)

Background: ATP Binding Cassette Transporters (ABCB1) gene plays an important role in transport of different metabolites and anticancer drugs across the cell membrane. There is lack of knowledge on ABCB1 gene polymorphism and its correlation with Adriamycin or paclitaxel based chemotherapy induced toxicity in breast cancer patients. Therefore in this study, we explored the correlation of ABCB1 polymorphisms gene on response and toxicity in adriamycin and paclitaxel based chemotherapy in breast cancer patients from Indian population., Methods: Two hundred BC patients receiving Adriamycin and paclitaxel chemotherapy were enrolled in this study and chemotherapy induced hematological and non-hematological toxicity reactions were noted. The polymorphisms in ABCB1 gene (C1236T, C3435T) were studied by PCR and RFLP analysis., Results: The univariate logistic regression analysis showed statistically significant negative association with protective effects of ABCB1 (C3435T) polymorphism with heterozygous genotype (OR=0.34, 95% CI: 0.13-0.89; p=0.027), homozygous variant genotype (OR=0.31, 95% CI: 0.10-0.99; p=0.049) and combined C/T+T/T genotypes (OR=0.33, 95% CI: 0.13-0.79; p=0.013) in relation with severe toxicity of chemotherapy induced nausea and vomiting in breast cancer patients treated with Adriamycin chemotherapy. The 3435 C>T polymorphism of ABCB1 gene with heterozygous C/T genotype showed significantly negative association (OR=0.37, 95% CI: 0.14-0.96; p=0.042) with peripheral neuropathy in patients treated primarily with paclitaxel thereafter Adriamycin., Conclusion: The findings obtained from this study revealed significant association of ABCB1 3435 C>T polymorphisms with non-hematological toxicity in response to adriamycin and paclitaxel based chemotherapy.

Background: Imatinib mesylate (IM) is a first-line treatment option for the majority of patients diagnosed with gastrointestinal stromal tumors (GISTs). Although the clinical benefit is high, interindividual response is variable. This study thus aimed to assess how genetic polymorphisms can affect the blood levels of IM and treatment outcomes in patients with GIST., Methods: A total of 31 single-nucleotide polymorphisms (SNPs) in selected cytochrome P450 ( P450 ), ATP-binding cassette transporter ( ABC ), solute carrier family ( SLC ), interleukin-4 receptor ( IL4R ), and vascular endothelial growth factor ( VEGF ) genes were genotyped using an SNP mass array platform. A total of 192 consecutive patients with GIST who received 400 mg of IM daily were enrolled into the study, with 1,485 blood samples being analyzed. According to genotypes, IM trough concentrations were tested and compared. Progression-free survival (PFS) and overall survival (OS) were also assessed., Results: With a mean follow-up of 75.99 months, trough concentrations of imatinib were examined at average time points of 7.73 for each patient. Polymorphism in ABCB1 rs1045642 was found to be associated with steady-state IM trough plasma levels (P=0.008). Patients with the C genotype (CT + CC) of rs1045642 exhibited higher IM trough concentrations (1,271.09±306.69 ng/mL) compared to those with the TT genotype (1,106.60±206.05 ng/mL). No statistically significant differences in IM plasma concentration were observed for the other SNPs tested. None of the tested SNPs displayed a significant association with patients' survival in this study., Conclusions: This is the largest cohort study evaluating the associations of SNP and imatinib blood trough levels. The ABCB1 rs1045642 genetic polymorphism may exert an effect on the pharmacokinetics of imatinib. The presence of the C allele in ABCB1 rs1045642 is predictive of a higher plasma concentration of IM., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-188/coif). The authors have no conflicts of interest to declare., (2024 Journal of Gastrointestinal Oncology. All rights reserved.)

Prostate cancer (PCa) is the second leading cause of cancer-related death in American men. PCa that relapses after hormonal therapies, referred to as castration resistant PCa (CRPC), often presents with metastases (mCRPC) that are the major cause of mortality. The few available therapies for mCRPC patients include taxanes docetaxel (DTX) and cabazitaxel (CBZ). However, development of resistance limits their clinical use. Mechanistically, resistance arises through upregulation of multidrug resistance (MDR) proteins such as MDR1/ABCB1, making ABCB1 an attractive therapeutic target. Yet, ABCB1 inhibitors failed to be clinically useful due to low specificity and toxicity issues. To study taxanes resistance, we produced CBZ resistant C4-2B cells (RC4-2B) and documented resistance to both CBZ and DTX in cell culture and in 3D prostaspheres settings. RNAseq identified increased expression of ABCB1 in RC4-2B, that was confirmed by immunoblotting and immunofluorescent analysis. ABCB1-specific inhibitor elacridar reversed CBZ and DTX resistance in RC4-2B cells, confirming ABCB1-mediated resistance mechanism. In a cell-based screen using a curated library of FDA-approved cytotoxic drugs, we found that DNA damaging compounds Camptothecin (CPT) and Cytarabine (Ara-C) overcame resistance as seen by similar cytotoxicity in parental C4-2B and resistant RC4-2B. Further, these compounds were cytotoxic to multiple PC cells resistant to taxanes with high ABCB1 expression and, therefore, can be used to conquer the acquired resistance to taxanes in PCa. Finally, inhibition of CDK4/6 kinases with small molecule inhibitors (CDK4/6i) potentiated cytotoxic effect of CPT or Ara-C in both parental and resistant cells. Overall, our findings indicate that DNA damaging agents CPT and Ara-C alone or in combination with CDK4/6i can be suggested as a new treatment regimen in CRPC patients, including those that are resistant to taxanes.