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With the development of the social economy, we are exposed to increasing noise in our daily lives. Our previous work found an ABCC1(NM_004996.3:c.A1769G, NP_004987.2:p.N590S) variant which cosegregated with the patients in an autosomal dominant non‐syndromic hearing loss family. At present, the specific mechanism of deafness caused by ABCC1 mutation is still not clear. Using the knock‐in mouse model simulating human ABCC1 mutation, we found that the occurrence of family‐related phenotypes was likely attributed to the combination of the mouse genotype and low‐intensity noise. GSH and GSSG are important physiological substrates of ABCC1. The destruction of GSH‐GSSG balance in the cochleae of both Abcc1N591S/+ mice and Abcc1N591S/N591S mice during low‐intensity noise exposure may result in irreversible damage to the hair cells of the cochleae, consequently leading to hearing loss in mice. The findings offered a potential novel idea for the prevention and management of hereditary hearing loss within this family. [ABSTRACT FROM AUTHOR]

Abstract Background In non-small cell lung cancer (NSCLC) the efficacy of chemo-immunotherapy is affected by the high expression of drug efflux transporters as ABCC1 and by the low expression of ABCA1, mediating the isopentenyl pyrophosphate (IPP)-dependent anti-tumor activation of Vγ9Vδ2 T-lymphocytes. In endothelial cells ABCA1 is a predicted target of the transcription factor EB (TFEB), but no data exists on the correlation between TFEB and ABC transporters involved in the chemo-immuno-resistance in NSCLC. Methods The impact of TFEB/ABCC1/ABCA1 expression on NSCLC patients’ survival was analyzed in the TCGA-LUAD cohort and in a retrospective cohort of our institution. Human NSCLC cells silenced for TFEB (shTFEB) were analyzed for ABC transporter expression, chemosensitivity and immuno-killing. The chemo-immuno-sensitizing effects of nanoparticles encapsulating zoledronic acid (NZ) on shTFEB tumors and on tumor immune-microenvironment were evaluated in Hu-CD34+ mice by single-cell RNA-sequencing. Results TFEBlowABCA1lowABCC1high and TFEBhighABCA1highABCC1low NSCLC patients had the worst and the best prognosis, respectively, in the TCGA-LUAD cohort and in a retrospective cohort of patients receiving platinum-based chemotherapy or immunotherapy as first-line treatment. By silencing shTFEB in NSCLC cells, we demonstrated that TFEB was a transcriptional inducer of ABCA1 and a repressor of ABCC1. shTFEB cells had also a decreased activity of ERK1/2/SREBP2 axis, implying reduced synthesis and efflux via ABCA1 of cholesterol and its intermediate IPP. Moreover, TFEB silencing reduced cholesterol incorporation in mitochondria: this event increased the efficiency of OXPHOS and the fueling of ABCC1 by mitochondrial ATP. Accordingly, shTFEB cells were less immuno-killed by the Vγ9Vδ2 T-lymphocytes activated by IPP and more resistant to cisplatin. NZ, which increased IPP efflux but not OXPHOS and ATP production, sensitized shTFEB immuno-xenografts, by reducing intratumor proliferation and increasing apoptosis in response to cisplatin, and by increasing the variety of anti-tumor infiltrating cells (Vγ9Vδ2 T-lymphocytes, CD8+T-lymphocytes, NK cells). Conclusions This work suggests that TFEB is a gatekeeper of the sensitivity to chemotherapy and immuno-killing in NSCLC, and that the TFEBlowABCA1lowABCC1high phenotype can be predictive of poor response to chemotherapy and immunotherapy. By reshaping both cancer metabolism and tumor immune-microenvironment, zoledronic acid can re-sensitize TFEBlow NSCLCs, highly resistant to chemo- and immunotherapy.

Background: In non-small cell lung cancer (NSCLC) the efficacy of chemo-immunotherapy is affected by the high expression of drug efflux transporters as ABCC1 and by the low expression of ABCA1, mediating the isopentenyl pyrophosphate (IPP)-dependent anti-tumor activation of Vγ9Vδ2 T-lymphocytes. In endothelial cells ABCA1 is a predicted target of the transcription factor EB (TFEB), but no data exists on the correlation between TFEB and ABC transporters involved in the chemo-immuno-resistance in NSCLC. Methods: The impact of TFEB/ABCC1/ABCA1 expression on NSCLC patients' survival was analyzed in the TCGA-LUAD cohort and in a retrospective cohort of our institution. Human NSCLC cells silenced for TFEB (shTFEB) were analyzed for ABC transporter expression, chemosensitivity and immuno-killing. The chemo-immuno-sensitizing effects of nanoparticles encapsulating zoledronic acid (NZ) on shTFEB tumors and on tumor immune-microenvironment were evaluated in Hu-CD34+ mice by single-cell RNA-sequencing. Results: TFEBlowABCA1lowABCC1high and TFEBhighABCA1highABCC1low NSCLC patients had the worst and the best prognosis, respectively, in the TCGA-LUAD cohort and in a retrospective cohort of patients receiving platinum-based chemotherapy or immunotherapy as first-line treatment. By silencing shTFEB in NSCLC cells, we demonstrated that TFEB was a transcriptional inducer of ABCA1 and a repressor of ABCC1. shTFEB cells had also a decreased activity of ERK1/2/SREBP2 axis, implying reduced synthesis and efflux via ABCA1 of cholesterol and its intermediate IPP. Moreover, TFEB silencing reduced cholesterol incorporation in mitochondria: this event increased the efficiency of OXPHOS and the fueling of ABCC1 by mitochondrial ATP. Accordingly, shTFEB cells were less immuno-killed by the Vγ9Vδ2 T-lymphocytes activated by IPP and more resistant to cisplatin. NZ, which increased IPP efflux but not OXPHOS and ATP production, sensitized shTFEB immuno-xenografts, by reducing intratumor proliferation and increasing apoptosis in response to cisplatin, and by increasing the variety of anti-tumor infiltrating cells (Vγ9Vδ2 T-lymphocytes, CD8+T-lymphocytes, NK cells). Conclusions: This work suggests that TFEB is a gatekeeper of the sensitivity to chemotherapy and immuno-killing in NSCLC, and that the TFEBlowABCA1lowABCC1high phenotype can be predictive of poor response to chemotherapy and immunotherapy. By reshaping both cancer metabolism and tumor immune-microenvironment, zoledronic acid can re-sensitize TFEBlow NSCLCs, highly resistant to chemo- and immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: This research investigates the challenge of drug resistance in non-small cell lung carcinoma (NSCLC) and how certain drugs, namely, tyrosine kinase inhibitors (TKIs), can induce multidrug resistance (MDR). This study aims to understand how patient-derived NSCLC cells respond to different TKIs and how genetic variations in patients may influence this response. The analysis of the efficacy of TKIs and their influence on the expression of specific markers associated with MDR shows that they elicit a different response in different NSCLC cells. Genetic alterations in signaling pathways associated with drug resistance likely contribute to the differential responses to TKIs. These findings underscore the importance of considering individual genetic profiles and performing thorough sensitivity testing to develop effective treatment strategies, particularly in the early stages of NSCLC, and highlight the potential for personalized cancer therapies. 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. [ABSTRACT FROM AUTHOR]

ATP-binding cassette (ABC) transporters play a crucial role for the efflux of a wide range of substrates across different cellular membranes. In the central nervous system (CNS), ABC transporters have recently gathered significant attention due to their pivotal involvement in brain physiology and neurodegenerative disorders, such as Alzheimer's disease (AD). Glial cells are fundamental for normal CNS function and engage with several ABC transporters in different ways. Here, we specifically highlight ABC transporters involved in the maintenance of brain homeostasis and their implications in its metabolic regulation. We also show new aspects related to ABC transporter function found in less recognized diseases, such as Huntington's disease (HD) and experimental autoimmune encephalomyelitis (EAE), as a model for multiple sclerosis (MS). Understanding both their impact on the physiological regulation of the CNS and their roles in brain diseases holds promise for uncovering new therapeutic options. Further investigations and preclinical studies are warranted to elucidate the complex interplay between glial ABC transporters and physiological brain functions, potentially leading to effective therapeutic interventions also for rare CNS disorders. [ABSTRACT FROM AUTHOR]

ABCC1 belongs to the ATP-binding cassette (ABC) superfamily, which encompasses a total of 48 constituent members. ABCC1 has been shown to be associated with the growth, progression, and drug resistance of various types of cancer. However, the impact of ABCC1 on cancer immune infiltration and pan-cancer prognosis has been rarely studied. Our comprehensive pan-cancer analysis unveiled elevated ABCC1 expression across various cancers. ABCC1 overexpression consistently predicted unfavorable outcomes based on TCGA data. Moreover, ABCC1 expression exhibited intricate associations with diverse immune-related genes and demonstrated a close correlation with immune scores across multiple tumor types. Analysis of scRNA-seq data from the GEO database revealed that the expression of ABCC1 in hepatocellular carcinoma (HCC) cells is significant positively correlated with macrophage infiltration. Furthermore, various in vitro and in vivo experiments substantiated the role of ABCC1 in promoting the progression of HCC, along with increased macrophage recruitment. Based on the results, we propose ABCC1 as a potentially valuable prognostic indicator and a prospective target for immune-based cancer therapies.

Lung cancer remains the leading cause of cancer death globally, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Multidrug resistance (MDR), often caused by ATP-binding cassette (ABC) transporters, represents a significant obstacle in the treatment of NSCLC. While genetic profiling has an important role in personalized therapy, functional assays that measure cellular responses to drugs are gaining in importance. We developed an automated microplate-based immunofluorescence assay for the evaluation of MDR markers ABCB1, ABCC1, and ABCG2 in cells obtained from NSCLC patients through high-content imaging and image analysis, as part of a functional diagnostic approach. This assay effectively discriminated cancer from non-cancer cells within mixed cultures, which is vital for accurate assessment of changes in MDR marker expression in different cell populations in response to anticancer drugs. Validation was performed using established drug-sensitive (NCI-H460) and drug-resistant (NCI-H460/R) NSCLC cell lines, demonstrating the assay's capacity to distinguish and evaluate different MDR profiles. The obtained results revealed wide-ranging effects of various chemotherapeutic agents on MDR marker expression in different patient-derived NSCLC cultures, emphasizing the need for MDR diagnostics in NSCLC. In addition to being a valuable tool for assessing drug effects on MDR markers in different cell populations, the assay can complement genetic profiling to optimize treatment. Further assay adaptations may extend its application to other cancer types, improving treatment efficacy while minimizing the development of resistance. [ABSTRACT FROM AUTHOR]

ATP-binding cassette (ABC) transporters play a crucial role for the efflux of a wide range of substrates across different cellular membranes. In the central nervous system (CNS), ABC transporters have recently gathered significant attention due to their pivotal involvement in brain physiology and neurodegenerative disorders, such as Alzheimer’s disease (AD). Glial cells are fundamental for normal CNS function and engage with several ABC transporters in different ways. Here, we specifically highlight ABC transporters involved in the maintenance of brain homeostasis and their implications in its metabolic regulation. We also show new aspects related to ABC transporter function found in less recognized diseases, such as Huntington’s disease (HD) and experimental autoimmune encephalomyelitis (EAE), as a model for multiple sclerosis (MS). Understanding both their impact on the physiological regulation of the CNS and their roles in brain diseases holds promise for uncovering new therapeutic options. Further investigations and preclinical studies are warranted to elucidate the complex interplay between glial ABC transporters and physiological brain functions, potentially leading to effective therapeutic interventions also for rare CNS disorders.

Simple Summary: Reusing drugs could potentially shorten the development time for the effective treatment of dementia. Here, we tested a drug—dimethyl fumarate—for its efficacy in reducing Alzheimer's disease-related changes in the brain. We discovered that the drug is not efficient due to the involvement of an essential exporting brain transporter. Alzheimer's disease (AD), the leading cause of dementia, is a growing health issue with very limited treatment options. To meet the need for novel therapeutics, existing drugs with additional preferred pharmacological profiles could be recruited. This strategy is known as 'drug repurposing'. Here, we describe dimethyl fumarate (DMF), a drug approved to treat multiple sclerosis (MS), to be tested as a candidate for other brain diseases. We used an APP-transgenic model (APPtg) of senile β-amyloidosis mice to further investigate the potential of DMF as a novel AD therapeutic. We treated male and female APPtg mice through drinking water at late stages of β-amyloid (Aβ) deposition. We found that DMF treatment did not result in modulating effects on Aβ deposition at this stage. Interestingly, we found that glutathione-modified DMF interacts with the ATP-binding cassette transporter ABCC1, an important gatekeeper at the blood–brain and blood–plexus barriers and a key player for Aβ export from the brain. Our findings suggest that ABCC1 prevents the effects of DMF, which makes DMF unsuitable as a novel therapeutic drug against AD. The discovered effects of ABCC1 also have implications for DMF treatment of multiple sclerosis. [ABSTRACT FROM AUTHOR]

Background: The ATP-Binding Cassette (ABC) transporter has long been studied to confer drug resistance in human tumors and play important role in metabolic processes and cellular signaling. The overexpression of ABCB1, ABCC1, ABCC2, ABCC3, and ABCG2 leads to decreased sensitivity of lung cancer to cisplatin. At the transcription level, the expression of ABC transporters is highly regulated and requires the complex interplay of factors involved in differentiation and development, cell survival and apoptosis upon intrinsic and environmental stress. The p53 regulation of drug-resistance genes is also complex yet not well understood. Previously, we demonstrated the synergistic interaction between bixin or fucoxanthin with cisplatin in A549 lung cancer cells. Objectives: Current study aims to identify whether carotenoids enhancing therapeutic effect of Cisplatin due to the ability to reverse drug resistance associated proteins, such as ABC transporter and regulating the tumor suppressor corresponding gene, p53. Methods: Real-Time Quantitative-Polymerase Chain Reaction (RT-qPCR) was performed to estimate the expression level of ABCC1 and ABCC2, and p53 of A549 cell lines in response to carotenoids alone and in combination with cisplatin. Results and Conclusion: The administration of bixin or fucoxanthin decreases the expression of ABCC1 and ABCC2. Both carotenoids, either alone or in combination with cisplatin, upregulated p53 gene expression indicating the mechanism of proliferation inhibition and apoptosis occurs via the p53 caspase-independent pathway.

Background: Lung cancer is a social problem of increasing concern, and non-small cell lung cancer (NSCLC) accounts for 80%–85% incidence of lung cancer. Cisplatin (DDP) is reported as a first-line chemotherapy drug for NSCLC, but the resistance has became a main obstacle for NSCLC treatment. The high level of circular RNA circ_0076305 was related to the DDP resistance in NSCLC. However, the mechanism of circ_0076305 remains unclear in DDP resistance of NSCLC. Materials and Methods: Exosomes were detected by a transmission electron microscope and nanoparticle tracking analysis. The protein levels of CD63, CD81, P-glycoprotein (P-gp), Lung resistance-related protein, and ATP-binding cassette subfamily C member 1 (ABCC1) were examined by Western blot assay. Circ_0076305, microRNA-186-5p (miR-186-5p), and ABCC1 levels were tested by real-time quantitative polymerase chain reaction. DDP resistance was examined by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide assay. The binding relationship between miR-186-5p and circ_0076305 or ABCC1 was predicted by circRNA interactome or starBase, and then verified by dual-luciferase reporter and RNA immunoprecipitation assays. The effect of circ_0076305 on DDP resistance in NSCLC was examined by xenograft tumor model in vivo. Results: Circ_0076305 was increased in NSCLC cell-derived exosomes, DDP-resistant NSCLC tissues and cells. Circ_0076305 knockdown elevated DDP sensitivity in vitro. Mechanically, circ_0076305 enhanced ABCC1 expression through sponging miR-186-5p, thus regulating DDP resistance of NSCLC. Furthermore, circ_0076305 silencing improved DDP sensitivity of NSCLC in vivo. Conclusion: The results from this study disclosed that circ_0076305 knockdown improved DDP sensitivity by the miR-186-5p/ABCC1 axis in NSCLC, hinting a potential circRNA-targeted therapy for NSCLC. [ABSTRACT FROM AUTHOR]

Antipsychotic (AP)—induced adverse drug reactions (ADRs) are a current problem of biological and clinical psychiatry. Despite the development of new generations of APs, the problem of AP-induced ADRs has not been solved and continues to be actively studied. One of the important mechanisms for the development of AP-induced ADRs is a genetically-determined impairment of AP efflux across the blood-brain barrier (BBB). We present a narrative review of publications in databases (PubMed, Springer, Scopus, Web of Science E-Library) and online resources: The Human Protein Atlas; GeneCards: The Human Gene Database; US National Library of Medicine; SNPedia; OMIM Online Mendelian Inheritance in Man; The PharmGKB. The role of 15 transport proteins involved in the efflux of drugs and other xenobiotics across cell membranes (P-gp, TAP1, TAP2, MDR3, BSEP, MRP1, MRP2, MRP3, MRP4, MRP5, MRP6, MRP7, MRP8, MRP9, BCRP) was analyzed. The important role of three transporter proteins (P-gp, BCRP, MRP1) in the efflux of APs through the BBB was shown, as well as the association of the functional activity and expression of these transport proteins with low-functional and non-functional single nucleotide variants (SNVs)/polymorphisms of the ABCB1, ABCG2, ABCC1 genes, encoding these transport proteins, respectively, in patients with schizophrenia spectrum disorders (SSDs). The authors propose a new pharmacogenetic panel "Transporter protein (PT)—Antipsychotic (AP) Pharmacogenetic test (PGx)" (PTAP-PGx), which allows the evaluation of the cumulative contribution of the studied genetic biomarkers of the impairment of AP efflux through the BBB. The authors also propose a riskometer for PTAP-PGx and a decision-making algorithm for psychiatrists. Conclusions: Understanding the role of the transportation of impaired APs across the BBB and the use of genetic biomarkers for its disruption may make it possible to reduce the frequency and severity of AP-induced ADRs, since this risk can be partially modified by the personalized selection of APs and their dosing rates, taking into account the genetic predisposition of the patient with SSD. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Liver neoplasm is one of the most fatal malignancies worldwide, among which hepatocellular carcinoma (HCC) (MIM #114550, https://omim.org/) is the most prevalent type. ABCC1 (MIM *158343) is a membrane- bound protein that relies on ATP hydrolysis to transport substrates and is associated with tumour drug resistance and malignant potential. However, the relationship between ABCC1, HCC prognosis, and immune infiltration remains elusive. MATERIALS AND METHODS: We analysed the mRNA expression of ABCC1 using data from public databases. Immunohistochemistry staining was performed to identify ABCC1 expression in tumour samples. We further investigated the correlation between ABCC1 and clinicopathological features. We investigated the connection between ABCC1 and HCC prognosis using survival and Cox regression analyses. We investigated the underlying pathways of ABCC1 in HCC using functional enrichment analysis and GSEA. We determine the relationship between ABCC1 and immune c ell infiltration via an integrated immune landscape analysis. RESULTS: Our investigation revealed the upregulation of ABCC1 expression in HCC (p < 0.01), which was verified in clinical samples (p < 0.01). In addition, ABCC1 is adversely associated with HCC clinical features and prognosis (p < 0.05). GO/KEGG analysis and GSEA identified that ABCC1 participates in multiple immuneand tumour-related pathways (p < 0.05). Immune cell infiltration analysis indicated that ABCC1 was positively correlated with various immune cells, among which, the strongest correlation was with macrophages (p < 0.001). Furthermore, we observed significant variations in immune checkpoints between the ABCC1-low and ABCC1-high groups (p < 0.01). This indicated that patients with a high expression of ABCC1 might respond poorly to immune checkpoint blockade (ICB) therapy (p = 9.2e-07). CONCLUSIONS: Our study identified ABCC1 as a predictor of HCC prognosis and response to therapy. [ABSTRACT FROM AUTHOR]

Background: For several decades, Black patients have carried a higher burden of laryngeal cancer among all races. Even when accounting for sociodemographics, a disparity remains. Differentially expressed microRNAs have been linked to racially disparate clinical outcomes in breast and prostate cancers, yet an association in laryngeal cancer has not been addressed. In this study, we present our computational analysis of differentially expressed miRNAs in Black compared with White laryngeal cancer and further validate microRNA-9-5p (miR-9-5p) as a potential mediator of cancer phenotype and chemoresistance. Methods: Bioinformatic analysis of 111 (92 Whites, 19 Black) laryngeal squamous cell carcinoma (LSCC) specimens from the TCGA revealed miRNAs were significantly differentially expressed in Black compared with White LSCC. We focused on miR-9-5 p which had a significant 4-fold lower expression in Black compared with White LSCC (p<0.05). After transient transfection with either miR-9 mimic or inhibitor in cell lines derived from Black (UM-SCC-12) or White LSCC patients (UM-SCC-10A), cellular migration and cell proliferation was assessed. Alterations in cisplatin sensitivity was evaluated in transient transfected cells via IC50 analysis. qPCR was performed on transfected cells to evaluate miR-9 targets and chemoresistance predictors, ABCC1 and MAP1B. Results: Northern blot analysis revealed mature miR-9-5p was inherently lower in cell line UM-SCC-12 compared with UM-SCC-10A. UM -SCC-12 had baseline increase in cellular migration (p < 0.01), proliferation (p < 0.0001) and chemosensitivity (p < 0.01) compared to UM-SCC-10A. Increasing miR-9 in UMSCC-12 cells resulted in decreased cellular migration (p < 0.05), decreased proliferation (p < 0.0001) and increased sensitivity to cisplatin (p < 0.001). Reducing miR-9 in UM-SCC-10A cells resulted in increased cellular migration (p < 0.05), increased proliferation (p < 0.05) and decreased sensitivity to cisplatin (p < 0.01). A significant inverse relationship in ABCC1 and MAP1B gene expression was observed whenmiR-9 levels were transiently elevated or reduced in either UMSCC-12 or UM-SCC-10A cell lines, respectively, suggesting modulation by miR-9. Conclusion: Collectively, these studies introduce differential miRNA expression in LSCC cancer health disparities and propose a role for low miR-9-5p as a mediator in LSCC tumorigenesis and chemoresistance. [ABSTRACT FROM AUTHOR]

BackgroundFor several decades, Black patients have carried a higher burden of laryngeal cancer among all races. Even when accounting for sociodemographics, a disparity remains. Differentially expressed microRNAs have been linked to racially disparate clinical outcomes in breast and prostate cancers, yet an association in laryngeal cancer has not been addressed. In this study, we present our computational analysis of differentially expressed miRNAs in Black compared with White laryngeal cancer and further validate microRNA-9-5p (miR-9-5p) as a potential mediator of cancer phenotype and chemoresistance.MethodsBioinformatic analysis of 111 (92 Whites, 19 Black) laryngeal squamous cell carcinoma (LSCC) specimens from the TCGA revealed miRNAs were significantly differentially expressed in Black compared with White LSCC. We focused on miR-9-5 p which had a significant 4-fold lower expression in Black compared with White LSCC (p

Background: The ATP-Binding Cassette (ABC) transporter has long been studied to confer drug resistance in human tumors and play important role in metabolic processes and cellular signaling. The overexpression of ABCB1, ABCC1, ABCC2, ABCC3, and ABCG2 leads to decreased sensitivity of lung cancer to cisplatin. At the transcription level, the expression of ABC transporters is highly regulated and requires the complex interplay of factors involved in differentiation and development, cell survival and apoptosis upon intrinsic and environmental stress. The p53 regulation of drugresistance genes is also complex yet not well understood. Previously, we demonstrated the synergistic interaction between bixin or fucoxanthin with cisplatin in A549 lung cancer cells. Objectives: Current study aims to identify whether carotenoids enhancing therapeutic effect of Cisplatin due to the ability to reverse drug resistance associated proteins, such as ABC transporter and regulating the tumor suppressor corresponding gene, p53. Methods: Real-Time Quantitative-Polymerase Chain Reaction (RT-qPCR) was performed to estimate the expression level of ABCC1 and ABCC2, and p53 of A549 cell lines in response to carotenoids alone and in combination with cisplatin. Results and Conclusion: The administration of bixin or fucoxanthin decreases the expression of ABCC1 and ABCC2. Both carotenoids, either alone or in combination with cisplatin, upregulated p53 gene expression indicating the mechanism of proliferation inhibition and apoptosis occurs via the p53 caspase-independent pathway. [ABSTRACT FROM AUTHOR]

Lung cancer remains the leading cause of cancer death globally, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Multidrug resistance (MDR), often caused by ATP-binding cassette (ABC) transporters, represents a significant obstacle in the treatment of NSCLC. While genetic profiling has an important role in personalized therapy, functional assays that measure cellular responses to drugs are gaining in importance. We developed an automated microplate-based immunofluorescence assay for the evaluation of MDR markers ABCB1, ABCC1, and ABCG2 in cells obtained from NSCLC patients through high-content imaging and image analysis, as part of a functional diagnostic approach. This assay effectively discriminated cancer from non-cancer cells within mixed cultures, which is vital for accurate assessment of changes in MDR marker expression in different cell populations in response to anticancer drugs. Validation was performed using established drug-sensitive (NCI-H460) and drug-resistant (NCI-H460/R) NSCLC cell lines, demonstrating the assay’s capacity to distinguish and evaluate different MDR profiles. The obtained results revealed wide-ranging effects of various chemotherapeutic agents on MDR marker expression in different patient-derived NSCLC cultures, emphasizing the need for MDR diagnostics in NSCLC. In addition to being a valuable tool for assessing drug effects on MDR markers in different cell populations, the assay can complement genetic profiling to optimize treatment. Further assay adaptations may extend its application to other cancer types, improving treatment efficacy while minimizing the development of resistance.

Huntington's disease (HD) is a lethal neurodegenerative disorder without efficient therapeutic options. The inefficient translation from preclinical and clinical research into clinical use is mainly attributed to the lack of (i) understanding of disease initiation, progression, and involved molecular mechanisms; (ii) knowledge of the possible HD target space and general data awareness; (iii) detailed characterizations of available disease models; (iv) better suitable models; and (v) reliable and sensitive biomarkers. To generate robust HD-like symptoms in a mouse model, the neomycin resistance cassette was excised from zQ175 mice, generating a new line: zQ175Δneo. We entirely describe the dynamics of behavioral, neuropathological, and immunohistological changes from 15–57 weeks of age. Specifically, zQ175Δneo mice showed early astrogliosis from 15 weeks; growth retardation, body weight loss, and anxiety-like behaviors from 29 weeks; motor deficits and reduced muscular strength from 36 weeks; and finally slight microgliosis at 57 weeks of age. Additionally, we collected the entire bioactivity network of small-molecule HD modulators in a multitarget dataset (HD_MDS). Hereby, we uncovered 358 unique compounds addressing over 80 different pharmacological targets and pathways. Our data will support future drug discovery approaches and may serve as useful assessment platform for drug discovery and development against HD. [ABSTRACT FROM AUTHOR]

Background: Triple-negative breast cancer (TNBC) is the most serious subtype of breast cancer (BC) and has been a great health threat to females. Although chemotherapeutic agent contributes a lot to TNBC treatment, drug resistance has been a great obstacle for chemotherapies. Ursolic acid (UA), a pentacyclic triterpenoid compound, was reported to reverse paclitaxel resistance in BC. However, whether UA could affect the resistance of TNBC cells to other drugs such as doxorubicin (DOX) remains to be discovered. Materials and Methods: MTT assay, EdU assay, colony formation assay, and flow cytometry analysis were implemented to detect the viability, proliferation, and apoptosis of DOX-resistant MDA-MB-468 and MDA-MB-436 cells with or without UA treatment. Mechanism assays including RIP, RNA pull-down, and luciferase reporter assays verified the interaction between RNAs. Results: UA treatment hindered the growth and mitigated the DOX resistance of DOX-resistant MDA-MB-468 and MDA-MB-436 cells. Mechanistically, multidrug resistance-associated protein 1 (ABCC1) expression was downregulated by UA treatment. MiR-186-5p was verified to target ABCC1. Further, UA-inhibited ZEB1-AS1 (zinc finger E-box binding homeobox 1 antisense RNA 1) was verified as a competitive endogenous RNA (ceRNA) to upregulate ABCC1 through sponging miR-186-5p. Importantly, UA treatment impaired the malignant phenotypes of DOX-resistant MDA-MB-468 and MDA-MB-436 cells through ZEB1-AS1/ABCC1 axis. Conclusion: UA promotes TNBC cell sensitivity to DOX through inactivating ZEB1-AS1/miR-186-5p/ABCC1 signaling. [ABSTRACT FROM AUTHOR]

Abstract Background Drug resistance is a major clinical drawback behind the failure of chemotherapy in non‐small cell lung cancer (NSCLC). In this study, we undertook to identify the precise role of circular RNA (circRNA) circ_0058357 in the functional properties of DDP‐resistant NSCLC cells. Methods Circ_0058357, miR‐361‐3p and ATP‐binding cassette (ABC) subfamily C member 1 (ABCC1) were quantified by qRT‐PCR and western blot. Cell survival and viability were gauged by MTT assay. Cell proliferation, apoptosis, invasion and migration were measured by EdU, flow cytometry, transwell and wound‐healing assays, respectively. The direct relationship between miR‐361‐3p and circ_0058357 or ABCC1 was validated by dual‐luciferase reporter assay. Results Our data showed that circ_0058357 was highly expressed in DDP‐resistant NSCLC tissues and cells. Inhibition of circ_0058357 repressed cell growth, invasion, migration, and promoted DDP sensitivity and cell apoptosis of H1299/DDP and A549/DDP cells in vitro. Moreover, inhibition of circ_0058357 diminished the growth of A549/DDP cells and sensitized them to the cytotoxic effect of DDP in vivo. Mechanistically, circ_0058357 contained a miR‐361‐3p binding site and miR‐361‐3p was identified as a molecular mediator of circ_0058357 regulation. MiR‐361‐3p suppressed ABCC1 expression by binding to ABCC1 3′UTR, and miR‐361‐3p‐mediated inhibition of ABCC1 affected the growth, invasion, migration, apoptosis and DDP sensitivity of H1299/DDP and A549/DDP cells. Furthermore, circ_0058357 regulated ABCC1 expression by competitively binding to shared miR‐361‐3p. Conclusions Our findings identified that inhibition of circ_0058357 suppresses the growth and metastasis of H1299/DDP and A549/DDP cells and sensitizes them to DDP therapy partially by targeting the miR‐361‐3p/ABCC1 axis.

The generation of tumor cells resistant to chemo- and radiation therapy is one of the unsolved problems of oncology. The study of the conditions and mechanisms of temozolomide (first-line drug in glioblastoma therapy) resistance formation is carried out on cultured cell lines. Considering the heterogeneity of glioblastomas, it is important to study the responses of different cell lines to temozolomide. The aim of this work was to obtain and characterize temozolomide-resistant T2 and T98G cell lines. The source of temozolomide was the drug Temodal® in lyophilized form for preparation of an infusion solution. T98G cells are known to be highly resistant to temozolomide; the response of T2 cells to the drug has not been studied yet. A single exposure to 1 mM temozolomide resulted in changes in T2 cell populations' content – an increase of the proportion of giant mononuclear cells and cells with fragmented nuclei. As a result, the number of cells in G0/G1 cell cycle phases decreased, while the number of polyploid cells increased by four times. The cells that reactivated proliferation were exposed to 2 mM temozolomide for the second and third times differed morphologically and in proliferation activity from the cells that underwent a single treatment, and approximated to the intact cells in many respects. After a single incubation with 2 mM temozolomide T2 cells reco-vered 90% monolayer in 48 days, after the second treatment—in 13 days, and after the third exposure—in 2 days only. Temozolomide resistance formation by T2 cells was not accompanied by changes in the initially high levels of multiple drug resistance genes ABCC1, ABCG2, and ABCB1 expression, as well as MGMT gene activity. The formation of temozolomide resistance in T2 glioblastoma cell culture is most likely due to the action of other mechanisms. Consequently, T2 cell line can provide a source of temozolomide-resistant cells and be used as a model of recurrent glioblastoma. T98G cells, as expected, showed an extremely high level of resistance to temozolomide. The drug at doses lower than 5 mM had no prominent effect on these cells. [ABSTRACT FROM AUTHOR]

Antineoplastic uptake by blast cells in acute myeloid leukemia (AML) could be influenced by influx and efflux transporters, especially solute carriers (SLCs) and ATP-binding cassette family (ABC) pumps. Genetic variability in SLC and ABC could produce interindividual differences in clinical outcomes. A systematic review was performed to evaluate the influence of SLC and ABC polymorphisms and their combinations on efficacy and safety in AML cohorts. Anthracycline intake was especially influenced by SLCO1B1 polymorphisms, associated with lower hepatic uptake, showing higher survival rates and toxicity in AML studies. The variant alleles of ABCB1 were related to anthracycline intracellular accumulation, increasing complete remission, survival and toxicity. Similar findings have been suggested with ABCC1 and ABCG2 polymorphisms. Polymorphisms of SLC29A1, responsible for cytarabine uptake, demonstrated significant associations with survival and response in Asian populations. Promising results were observed with SLC and ABC combinations regarding anthracycline toxicities. Knowledge of the role of transporter pharmacogenetics could explain the differences observed in drug disposition in the blast. Further studies including novel targeted therapies should be performed to determine the influence of genetic variability to individualize chemotherapy schemes. [ABSTRACT FROM AUTHOR]

Chemotherapy of soft tissue sarcomas (STS) is restricted by low chemosensitivity and multiple drug resistance (MDR). The purpose of our study was the analysis of MDR mechanism in different types of STS. We assessed the expression of ABC-transporters, MVP, YB-1, and analyzed their correlation with chemosensitivity of cancer cells. STS specimens were obtained from 70 patients without metastatic disease (2018–2020). Expression level of MDR-associated genes was estimated by qRT-PCR and cytofluorimetry. Mutations in ABC-transporter genes were captured by exome sequencing. Chemosensitivity (SI) of STS to doxorubicin (Dox), ifosfamide (Ifo), gemcitabine (Gem), and docetaxel (Doc) was analyzed in vitro. We found strong correlation in ABCB1, ABCC1, and ABCG2 expression. We demonstrated strong negative correlations in ABCB1 and ABCG2 expression with SI (Doc) and SI (Doc + Gem), and positive correlation of MVP expression with SI (Doc) and SI (Doc + Gem) in undifferentiated pleomorphic sarcoma. Pgp expression was shown in 5 out of 44 STS samples with prevalence of synovial sarcoma relapses and it is strongly correlated with SI (Gem). Mutations in MDR-associated genes were rarely found. Overall, STS demonstrated high heterogeneity in chemosensitivity that makes reasonable in vitro chemosensitivity testing to improve personalized STS therapy, and classic ABC-transporters are not obviously involved in MDR appearance. [ABSTRACT FROM AUTHOR]

Multidrug resistance protein 1 (MRP1/ABCC1) is an ATP-dependent efflux transporter, and responsible for the transport of a broad spectrum of xenobiotics, toxins, and physiological substrates across the plasma membrane. As an efflux pump, it plays a significant role in the absorption and disposition of drugs including anticancer drugs, antivirals, antimalarials, and antibiotics and their metabolites across physiological barriers in cells. MRP1 is also known to aid in the regulation of several physiological processes such as redox homeostasis, steroid metabolism, and tissue defense. However, its overexpression has been reported to be a key clinical marker associated with multidrug resistance (MDR) of several types of cancers including lung cancer, childhood neuroblastoma, breast and prostate carcinomas, often resulting in a higher risk of treatment failure and shortened survival rates in cancer patients. Aside MDR, overexpression of MRP1 is also implicated in the development of neurodegenerative and cardiovascular diseases. Due to the cellular importance of MRP1, the identification and biochemical/molecular characterization of modulators of MRP1 activity and expression levels are of key interest to cancer research and beyond. This review primarily aims at highlighting the physiological and pharmacological importance of MRP1, known MRP1 modulators, current challenges encountered, and the potential benefits of conducting further research on the MRP1 transporter. [ABSTRACT FROM AUTHOR]

Multidrug resistance protein 1 (MRP1/ABCC1) is an ATP-dependent efflux transporter, and responsible for the transport of a broad spectrum of xenobiotics, toxins, and physiological substrates across the plasma membrane. As an efflux pump, it plays a significant role in the absorption and disposition of drugs including anticancer drugs, antivirals, antimalarials, and antibiotics and their metabolites across physiological barriers in cells. MRP1 is also known to aid in the regulation of several physiological processes such as redox homeostasis, steroid metabolism, and tissue defense. However, its overexpression has been reported to be a key clinical marker associated with multidrug resistance (MDR) of several types of cancers including lung cancer, childhood neuroblastoma, breast and prostate carcinomas, often resulting in a higher risk of treatment failure and shortened survival rates in cancer patients. Aside MDR, overexpression of MRP1 is also implicated in the development of neurodegenerative and cardiovascular diseases. Due to the cellular importance of MRP1, the identification and biochemical/molecular characterization of modulators of MRP1 activity and expression levels are of key interest to cancer research and beyond. This review primarily aims at highlighting the physiological and pharmacological importance of MRP1, known MRP1 modulators, current challenges encountered, and the potential benefits of conducting further research on the MRP1 transporter.

Background: Drug resistance is a major clinical drawback behind the failure of chemotherapy in non‐small cell lung cancer (NSCLC). In this study, we undertook to identify the precise role of circular RNA (circRNA) circ_0058357 in the functional properties of DDP‐resistant NSCLC cells. Methods: Circ_0058357, miR‐361‐3p and ATP‐binding cassette (ABC) subfamily C member 1 (ABCC1) were quantified by qRT‐PCR and western blot. Cell survival and viability were gauged by MTT assay. Cell proliferation, apoptosis, invasion and migration were measured by EdU, flow cytometry, transwell and wound‐healing assays, respectively. The direct relationship between miR‐361‐3p and circ_0058357 or ABCC1 was validated by dual‐luciferase reporter assay. Results: Our data showed that circ_0058357 was highly expressed in DDP‐resistant NSCLC tissues and cells. Inhibition of circ_0058357 repressed cell growth, invasion, migration, and promoted DDP sensitivity and cell apoptosis of H1299/DDP and A549/DDP cells in vitro. Moreover, inhibition of circ_0058357 diminished the growth of A549/DDP cells and sensitized them to the cytotoxic effect of DDP in vivo. Mechanistically, circ_0058357 contained a miR‐361‐3p binding site and miR‐361‐3p was identified as a molecular mediator of circ_0058357 regulation. MiR‐361‐3p suppressed ABCC1 expression by binding to ABCC1 3′UTR, and miR‐361‐3p‐mediated inhibition of ABCC1 affected the growth, invasion, migration, apoptosis and DDP sensitivity of H1299/DDP and A549/DDP cells. Furthermore, circ_0058357 regulated ABCC1 expression by competitively binding to shared miR‐361‐3p. Conclusions: Our findings identified that inhibition of circ_0058357 suppresses the growth and metastasis of H1299/DDP and A549/DDP cells and sensitizes them to DDP therapy partially by targeting the miR‐361‐3p/ABCC1 axis. [ABSTRACT FROM AUTHOR]

Malignant tumors contribute significantly to human mortality. Chemotherapy is a commonly used treatment for tumors. However, due to the low selectivity of chemotherapeutic drugs, immune cells can be damaged during antitumor treatment, resulting in toxicity. Lipopolysaccharide (LPS) can stimulate immune cells to respond to foreign substances. Here, we found that 10 ng/mL LPS could induce tolerance to antitumor drugs in macrophages without altering the effect of the drugs on tumor cells. Differentially expressed genes (DEGs) were identified between cells before and after LPS administration using transcriptome sequencing and found to be mainly associated with ATP-binding cassette (ABC)-resistant transporters and glutathione S-transferase (GST). LPS was shown by qRT-PCR and western blotting to promote the expression of ABCC1, GSTT1, and GSTP1 by 38.3 %, 194.8 %, and 27.0 %. Furthermore, three inhibitors (inhibitors of GST, glutathione synthesis, and ABCC1) were used for further investigation, showing that these inhibitors reduced macrophage survival rates by 44.0 %, 52.3 %, and 43.3 %, while the intracellular adriamycin content increased by 28.9 %, 42.9 %, and 51.3 %, respectively. These findings suggest that the protective mechanism of LPS on macrophages is associated with increased GST activity, the consumption of glutathione, and increased expression of ABCC1 protein. Therefore, LPS has a potential role in enhancing immunity. • It is found for the first time that 10 ng/mL lipopolysaccharide could induce macrophages to tolerate damage caused by antitumor drugs without altering the effect of antitumor drugs on tumor cells • Through transcriptome sequencing, it is known that the protection mechanism of LPS is related to ABC and GST family. • The protection mechanism of LPS is to increase the activity of glutathione S-transferase enzyme, consume glutathione and efflux drugs by transporting drug-resistant protein ABCC1. [ABSTRACT FROM AUTHOR]

Multiple drug resistance (MDR), referring to the resistance of cancer cells to a broad spectrum of structurally and mechanistically unrelated drugs across membranes, severely impairs the response to chemotherapy and leads to chemotherapy failure. Overexpression of ATP binding cassette (ABC) transporters is a major contributing factor resulting in MDR, which can recognize and mediate the efflux of diverse drugs from cancer cells, thereby decreasing intracellular drug concentration. Therefore, modulators of ABC transporter could be used in combination with standard chemotherapeutic anticancer drugs to augment the therapeutic efficacy. This review summarizes the recent advances of important cancer-related ABC transporters, focusing on their physiological functions, structures, and the development of new compounds as ABC transporter inhibitors.

Circular RNAs (circRNAs) play vital roles in various types of cancer and chemosentivity. In the progression of carcinogenesis, exosomes are messengers for intercellular communication. The aim of this study was to explore the role of exosomal circRNA phosphatidylinositol-4-phosphate 5-kinase type 1 alpha (circ_PIP5K1A) in non-small cell lung cancer (NSCLC) progression and cisplatin sensitivity. The expression levels of circ_PIP5K1A, miR-101 and ATP binding cassette subfamily C member 1 (ABCC1) were detected by quantitative real-time polymerase chain reaction or western blot assay. Cell Counting Kit-8 assay was used to detect cell viability and 50% inhibitory concentration value of cisplatin. Cell migration, invasion, proliferation, and apoptosis were determined by wound healing assay, transwell assay, colony formation assay, and flow cytometry, respectively. A xenograft tumor model was established to explore the role of circ_PIP5K1A in vivo. Exosomes were detected using transmission electron microscopy analysis. The interaction between miR-101 and circ_PIP5K1A or ABCC1 was predicted by bioinformatics analysis and verified by dual-luciferase reporter assay and RNA pull-down assay. Circ_PIP5K1A and ABCC1 were overexpressed and miR-101 was downregulated in NSCLC tissues, serum samples, and cells. Knockdown of exosomal circ_PIP5K1A inhibited NSCLC cell proliferation, migration, and invasion and promoted apoptosis and cisplatin sensitivity. Likewise, circ_PIP5K1A downregulation inhibited tumor growth. MiR-101 was a direct target of circ_PIP5K1A, and its knockdown reversed the effects of circ_PIP5K1A silence on inhibition of NSCLC progression and promotion of cisplatin sensitivity. Moreover, ABCC1 was a downstream target of miR-101, and miR-101 overexpression inhibited the progression of NSCLC cells and increased cisplatin sensitivity by targeting ABCC1. Besides, circ_PIP5K1A positively regulated ABCC1 expression by sponging miR-101. Exosomal circ_PIP5K1A knockdown inhibited NSCLC progression and promoted cisplatin sensitivity by regulating miR-101/ABCC1 axis, providing a novel avenue for treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Juvenile common carp were treated with Cd2+ at a sublethal concentration for Cyprinidae (6.4 mg/L). The expression of N-methyl-D-aspartate receptor subunit genes (NR2A, NR2B) and ATP-binding cassette subfamily C member 1 gene (ABCC1) was compared between treated and untreated fish. In addition, cadmium accumulation in the fish tissues was assessed. NR2A was 18.9-fold upregulated by Cd2+ in the eyes (choroid + retina), which accumulated Cd, and was not upregulated in brain, which didn't accumulate Cd. This may have been caused by the blocking of calcium channels by Cd2+, which has a very similar ionic radius to that of Ca2+. ABCC1 was 2.6-fold upregulated in gills and was not upregulated in liver; both tissues accumulated high levels of Cd. This difference may have been caused by the accumulation of predominantly previously inactivated Cd in liver or by some difference in the mechanisms of self-detoxification from Cd2+ in fish gills and liver. [ABSTRACT FROM AUTHOR]

Background: ATP-binding cassette (ABC) transporters are responsible for the efflux of a wide variety of anti-cancer agents and have been implicated in the chemoresistance of various solid tumors. Chemoresistance is a major cause of therapeutic failure, especially in the highly aggressive triple-negative breast cancer (TNBC) in which, unlike estrogen receptor-expressing (ER+) BC, both endocrine and targeted treatments are ineffectual. We aimed to investigate the level and frequency of expression of the three most important ABC transporter, ABCG2, ABCC1, and ABCB1, according to breast cancer subtype. Methods: We evaluated ABCG2, ABCC1, and ABCB1 protein expressions in 124 primary breast tumors (78 samples were classified as TNBC, while 46 were classified as ER+) by immunohistochemistry and correlated it to clinicopathological characteristics and outcome. Results: All three transporters had significantly higher expression and were more frequently expressed in TNBC compared to ER+ tumors (p < 0.0001). ABCG2 and ABCC1 had a very high level of expression in TNBC that was significantly greater compared to ABCB1 (p < 0.0001). ABCB1 expression was associated with TNBC metastatic spread (p = 0.03). In contrast, TNBC patients with high ABCG2 expression level had significantly longer disease-free interval (p = 0.03) and overall survival (p = 0.007). Conclusion: ABCG2, ABCC1, and ABCB1 expression in breast cancer is subtype-specific and associated with triple-negative tumors. The expression of ABCB1 may be useful as a marker of metastatic spread. Moreover, unexpectedly, our results showed a beneficial effect of ABCG2 expression on TNBC clinical behavior. These findings could have implications for the implementation of future TNBC treatment strategies. [ABSTRACT FROM AUTHOR]

Background: The identification of genetic risk factors for Acute Lymphoblastic Leukemia (ALL), are increasingly urgent and necessary.Objective: The purpose of this study is to determine the association of the genetic polymorphisms ABCC1 rs3743527, NCF4 rs1883112 and CBR3 rs1056892 with ALL.Methods: DNA samples were obtained in 71 children with ALL (from 2 to 18 years) and in 71 controls without ALL, to determine the polymorphisms by real-time polymerase chain reaction (qPCR), using specific TaqMan probes in a StepOne® thermal cycler (Applied Biosystems, United States).Results: The results of the Odds Ratio analysis show that in the rs1883112 polymorphism of the NCF4 gene, the heterozygous allele has a risk effect for ALL (OR = 3.1870, CI = 1.8880–7.9383 and p = 0.0002), in turn the mutated genotype (AA) is associated with a protective effect (OR = 0.26, 0.1248 to 0.5434 and p = 0.0003). On the other hand, the CBR3 rs1056892 polymorphism shows a significant association of risk to ALL, in the presence of the HT genotype (OR = 2.77, IC = 1.3837 to 5.5651 and p = 0.004) and the mutated genotype of this polymorphism has a significant association with protection to ALL in the HM genotype (OR = 0.52, IC = 0.2639 to 1.0304 and p = 0.05). While the inheritance models of the polymorphisms let us see that of the rs1883112 polymorphism of the NCF4 polymorphism; the HT genotype of the codominant model shows a protective effect against ALL (OR = 0.4117, IC = 0.1718 to 0.9866 and p = 0.04), the recessive model shows us and confirms what we already saw in table number 3, being that there is an association with protective effect in the HM genotype (OR = 0.2604, IC = 0.1248 to 0.5434 and p = 0.0003). In the polymorphism rs1056892 of the CBR3 gene, a protection association was found in the heterozygous allele of the codominant model (OR = 0.3448, IC = 0.1375 to 0.8896 and p = 0.0274). In addition, the recessive inheritance model for the HM genotype shows a protective effect to ALL, (OR = 0.52, CI = 0.9919 to 3.8638 and p = 0.05).Conclusion: There is an evident impact of the NCF4 rs1883112 and CBR3 rs1056892 polymorphisms with an increased risk of susceptibility to ALL; Likewise, through the codominant inheritance model, the effect of the variation of the CBR3 rs1056892 gene as a protective factor against ALL was evaluated.

The organic anion transporter Adenosine triphosphate binding cassette subfamily C member 1 (ABCC1), also known as MRP1, has been demonstrated in murine models of Alzheimer's disease (AD) to export amyloid beta (Abeta) from the endothelial cells of the blood–brain barrier to the periphery, and that pharmaceutical activation of ABCC1 can reduce amyloid plaque deposition in the brain. Here, we show that ABCC1 is not only capable of exporting Abeta from the cytoplasm of human cells, but also that its overexpression significantly reduces Abeta production and increases the ratio of alpha- versus beta-secretase mediated cleavage of the amyloid precursor protein (APP), likely via indirect modulation of alpha-, beta- and gamma-secretase activity.

Antineoplastic uptake by blast cells in acute myeloid leukemia (AML) could be influenced by influx and efflux transporters, especially solute carriers (SLCs) and ATP-binding cassette family (ABC) pumps. Genetic variability in SLC and ABC could produce interindividual differences in clinical outcomes. A systematic review was performed to evaluate the influence of SLC and ABC polymorphisms and their combinations on efficacy and safety in AML cohorts. Anthracycline intake was especially influenced by SLCO1B1 polymorphisms, associated with lower hepatic uptake, showing higher survival rates and toxicity in AML studies. The variant alleles of ABCB1 were related to anthracycline intracellular accumulation, increasing complete remission, survival and toxicity. Similar findings have been suggested with ABCC1 and ABCG2 polymorphisms. Polymorphisms of SLC29A1, responsible for cytarabine uptake, demonstrated significant associations with survival and response in Asian populations. Promising results were observed with SLC and ABC combinations regarding anthracycline toxicities. Knowledge of the role of transporter pharmacogenetics could explain the differences observed in drug disposition in the blast. Further studies including novel targeted therapies should be performed to determine the influence of genetic variability to individualize chemotherapy schemes.

Nicotinamide phosphoribosyltransferase (NAMPT) is a rate‐limiting enzyme for nicotinamide adenine dinucleotide (NAD) synthesis and is involved in cancer cell proliferation through regulation of energy production pathways. Therefore, NAMPT inhibitors are promising drugs for cancer therapy by limiting energy supply of tumours. Herein, we demonstrated that the NAMPT inhibitor FK866 ((E)‐N‐(4‐(1‐Benzoylpiperidin‐4‐yl)butyl)‐3‐(pyridin‐3‐yl)acrylamide) dose‐dependently inhibited growth and cell motility of DU‐145 prostate tumour spheroids and decreased the intracellular ATP concentration. The apoptosis marker cleaved caspase‐3 remained unchanged, but the autophagy marker microtubule‐associated protein 1A/1B‐light chain 3 (LC3) was upregulated. Growth inhibition was reversed upon co‐administration of NAD to the cell culture medium. FK866 decreased calcein as well as pheophorbide A efflux from tumour spheroids and increased doxorubicin toxicity, indicating interference with function of drug efflux transporters. DU‐145 multicellular tumour spheroids expressed the stem cell associated markers CD133, CD44, Oct4, Nanog, Sox2, and drug transporters ABCB1, ABCG2, and ABCC1 which are associated with stem cell properties in cancer cells. The ABCB1 inhibitor zosuquidar, the ABCG2 inhibitor Ko143, and the ABCC1 inhibitor MK571 increased calcein retention. Neither protein expression of stem cell markers, nor drug transporters was significantly changed upon FK866 treatment. In conclusion, our data suggest that FK866 inhibits prostate cancer cell proliferation by interference with the energy metabolism, and function of drug efflux transporters. [ABSTRACT FROM AUTHOR]

Recurrence and metastasis remain the major cause of cancer mortality. Even for early-stage lung cancer, adjuvant chemotherapy yields merely slight increase to patient survival. EF-hand domain-containing protein D2 (EFHD2) has recently been implicated in recurrence of patients with stage I lung adenocarcinoma. In this study, we investigated the correlation between EFHD2 and chemoresistance in non-small cell lung cancer (NSCLC). High expression of EFHD2 was significantly associated with poor overall survival of NSCLC patients with chemotherapy in in silica analysis. Ectopic EFHD2 overexpression increased cisplatin resistance, whereas EFHD2 knockdown improved chemoresponse. Mechanistically, EFHD2 induced the production of NADPH oxidase 4 (NOX4) and in turn the increase of intracellular reactive oxygen species (ROS), consequently activating membrane expression of the ATP-binding cassette subfamily C member 1 (ABCC1) for drug efflux. Non-steroidal anti-inflammatory drug (NSAID) ibuprofen suppressed EFHD2 expression by leading to the proteasomal and lysosomal degradation of EFHD2 through a cyclooxygenase (COX)-independent mechanism. Combining ibuprofen with cisplatin enhanced antitumor responsiveness in a murine xenograft model in comparison with the individual treatment. In conclusion, we demonstrate that EFHD2 promotes chemoresistance through the NOX4-ROS-ABCC1 axis and therefore developing EFHD2-targeting strategies may offer a new avenue to improve adjuvant chemotherapy of lung cancer.

Sorafenib is a small molecule that blocks tumor proliferation by targeting the activity of multi-kinases for the treatment of advanced hepatocellular carcinoma (HCC). Increasing sorafenib resistance following long-term treatment is frequently encountered. Mechanisms underlying sorafenib resistance remain not completely clear. To further understand the mechanism of sorafenib resistance in HCC, we established sorafenib-resistant cell lines by slowly increasing sorafenib concentration in cell culture medium. Upregulation of USP22 and ABCC1 were found in Sorafenib-resistant cells. Sorafenib-resistant cells treated with USP22 siRNA showed significant reduction in endogenous mRNA and protein levels of ABCC1. During sorafenib treatment, upregulation of USP22 increases ABCC1 expression and subsequently contributes to sorafenib resistance in HCC cells. Immunohistochemical analysis revealed a positive correlation between USP22 and ABCC1 expression in tissue samples from sorafenib-resistant patients (Pearson’s correlation = 0.59, p = 0.03). Our findings indicate that upregulation of USP22 and ABCC1 expression during treatment contribute to sorafenib resistance in HCC cells and that USP22 has strong potential as a therapeutic target for overcoming sorafenib resistance in HCC patients.

Rab GTPases are important regulators of intracellular trafficking, having distinct intracellular localisation for controlling endocytic, exocytic, and recycling pathways. The impairments in Rab pathways have been linked with drug resistance in various cancers. However, the role of Rab21, an endocytic Rab GTPase, in the emergence of drug resistance is not known. Therefore, we aimed to investigate the role of Rab21 in MRP-1, drug efflux pump, mediated resistance in prostate cancer cells. Drug sensitive (PC-3/Wt) and epirubicin resistant (PC-3/Res) prostate cancer cell lines were used in this study. Our data revealed that PC-3/Res cells had high expression of MRP-1 mRNA and protein in comparison with PC-3/Wt cells. MRP-1 was found distributed between intracellular and cell surface pools in PC-3/Res cells and was capable of drug efflux as shown by doxorubicin and epirubicin efflux assays. Moreover, qRT-PCR and Western blot analysis showed that PC-3/Res cells also had significantly up-regulated expression of Rab21. To study the effect of Rab21 on MRP-1 mediated multidrug resistance, siRNA mediated knockdown of Rab21 was performed. Results showed that the knocking down of Rab21 decreased the drug efflux ability of PC-3/Res cells, possibly by altering the surface localisation of MRP-1. These results suggest that interruption in MRP-1 trafficking to the plasma membrane by Rab21 is a potential strategy to overcome multi drug resistance in cancer cells. [ABSTRACT FROM AUTHOR]

Glioma is the most common primary malignant tumour in the brain; temozolomide (TMZ) is the most prevalent chemotherapeutic drug currently used to combat this cancer. We reported previously that the long intergenic non‐protein coding RNA 470 (LINC00470) is a novel prognostic biomarker for glioma and promotes the tumour growth in an intracranial transplantation mouse model. However, the effects of LINC00470 on glioma cell proliferation, invasion and TMZ chemosensitivity, as well as its molecular mechanism, remain unclear. In this study, we found elevated expression levels of LINC00470 and MYC in glioma tissues and cells and decreased expression of microRNA‐134 (miR‐134). Functional studies have shown that LINC00470 promotes proliferation and invasion, and attenuates chemosensitivity of glioma cells, while miR‐134 exerts the opposite effect. In the rescue experiments, the tumorigenic effect of LINC00470 was offset by miR‐134. In the mechanism study, we found that LINC00470 was a competitive endogenous RNA (ceRNA) of miR‐134 and that miR‐134 can directly target MYC and negatively regulate its expression. Furthermore, MYC was positively correlated with ATP‐binding cassette subfamily C member 1 (ABCC1) expression in glioma cells and MYC up‐regulated ABCC1 expression. Further studies found that LINC00470 regulated MYC by sponging miR‐134 to regulate the expression of ABCC1. We concluded that LINC00470 promoted the expression of MYC and ABCC1 by suppressing miR‐134, thus promoting glioma cell proliferation and invasion, and attenuating TMZ chemosensitivity. Moreover, the LINC00470/miR‐134/MYC/ABCC1 axis constitutes a potential therapeutic target. [ABSTRACT FROM AUTHOR]

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Irina Piatkov, Dorgival Caetano, Yolinda Assur, Sue Lynn Lau, Trudi Jones, Steven C Boyages, Mark McLean University Clinic and Research Centre Blacktown, Western Sydney University, Western Sydney Local Health District, Blacktown, NSW, Australia Abstract: Clozapine (CZ) has superior efficacy to other antipsychotic agents in the treatment of schizophrenia and has been extensively used in clinical practice. ATP-binding cassette (ABC) transporter proteins are responsible for the distribution of various molecules as well as drugs across extracellular and intracellular membranes, including the blood–brain barrier. Genetic variations in these proteins can account for differences in treatment response. We investigated the influence of ABCB1 rs1045642 and ABCC1 rs212090 single-nucleotide polymorphisms (SNPs) on CZ serum level, clinical outcome, and changes in body mass index (BMI) in the first year of CZ treatment. These polymorphisms influenced baseline BMI in males (p=0.009 and 0.054, B1 and C1, respectively), changes in BMI in males after 3 (p=0.026, ABCB1) and 12 months (p=0.022, ABCC1) of CZ treatment, and level of diastolic pressure (p=0.002 and 0.051, respectively). The combination of ABCB1 + ABCC1 homozygote SNPs was associated with increased CZ and norclozapine serum levels (p=0.054 and 0.010, respectively). ABC transporter SNPs could be potential biomarkers for CZ-induced weight gain and cardiovascular complications. Further pharmacogenetic research is warranted to help clinicians with their treatment decision, including concomitant use of drugs and prevention of side effects. Keywords: ABC transporters, weight gain, blood pressure, rs1045642, rs212090

ABCC1 belongs to the ATP-binding cassette (ABC) superfamily, which encompasses a total of 48 constituent members. ABCC1 has been shown to be associated with the growth, progression, and drug resistance of various types of cancer. However, the impact of ABCC1 on cancer immune infiltration and pan-cancer prognosis has been rarely studied. Our comprehensive pan-cancer analysis unveiled elevated ABCC1 expression across various cancers. ABCC1 overexpression consistently predicted unfavorable outcomes based on TCGA data. Moreover, ABCC1 expression exhibited intricate associations with diverse immune-related genes and demonstrated a close correlation with immune scores across multiple tumor types. Analysis of scRNA-seq data from the GEO database revealed that the expression of ABCC1 in hepatocellular carcinoma (HCC) cells is significant positively correlated with macrophage infiltration. Furthermore, various in vitro and in vivo experiments substantiated the role of ABCC1 in promoting the progression of HCC, along with increased macrophage recruitment. Based on the results, we propose ABCC1 as a potentially valuable prognostic indicator and a prospective target for immune-based cancer therapies., 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. Published by Elsevier Inc.)

In the process of chemotherapy, drug resistance of cancer cells is a common and difficult problem of chemotherapy failure, and it is also the main cause of cancer recurrence and metastasis. Non-coding RNAs (ncRNAs) refer to the RNA that does not encode proteins, including microRNA (miRNA), long non-coding RNA (lncRNA) and circularRNA (circRNA), etc. NcRNAs are involved in a series of important life processes and further regulate the expression of ABCC1 by directly or indirectly up-regulating or down-regulating the expression of targeted mRNAs, making cancer cells more susceptible to drug resistance. A growing number of studies have shown that ncRNAs have effects on cancer cell proliferation, invasion, metastasis, and drug sensitivity, by regulating the expression of ABCC1. In this review, we will discuss the emerging roles of ncRNAs regulating ABCC1 in chemotherapy resistance and mechanisms to reverse drug resistance as well as provide potential targets for future cancer treatment.

Multiple drug resistance (MDR) is characterized by the resistance of cancer cells to a broad spectrum of anticancer drugs. The main mechanism underlying the MDR phenotype is the overexpression of ATP-binding cassette (ABC) transporters by promoting active drug efflux from cancer cells. Some small-molecule protein kinase inhibitors have been found to overcome MDR by inhibiting ABC transporters as substrates or modulators. This study investigated the chemical activity of 58 FDA-approved anticancer kinase inhibitors against three multidrug resistance-related proteins. The studied proteins are ATP-Binding Cassette Sub-Family B Member 1 (ABCB1), ATP-Binding Cassette Subfamily C Member 1 (ABCC1), and ATP-binding cassette superfamily G member 2 (ABCG2). The drug-binding domain and ATP binding sites of the proteins were considered the kinase inhibitors' probable target. High-throughput virtual screening and molecular docking were employed to find the hit drugs, and the drugs with the highest binding affinity were further evaluated using the molecular dynamics (MD) simulation. The virtual screening revealed that several kinase inhibitors could be considered potential inhibitors of ABCB1, ABCC1, and ABCG2, among which larotrectinib, entrectinib, and infigratinib showed the highest binding affinity, respectively. Based on the obtained results from MD simulation, these drugs can form strong interactions with the essential residues of the target proteins. In silico investigation revealed that larotrectinib, entrectinib, and infigratinib can target the key residues of the studied proteins. Therefore, these approved kinase inhibitors could be considered potential therapies for MDR cancers by targeting these transporters.Communicated by Ramaswamy H. Sarma.

Multidrug resistance proteins (MRPs), members of the ATP-binding cassette transporter (ABC transporter) family, are pivotal for transporting endo- and xenobiotics, which confer resistance to anticancer agents and contribute to the clearance of oxidative products. However, their function in many biological processes is still unclear. We investigated the role of an evolutionarily conserved MRP in metabolic homeostasis by knocking down the expression of Drosophila multidrug-resistance like protein 1 (MRP) in several tissues involved in regulating metabolism, including the gut, fat body, and Malpighian tubules. Interestingly, only suppression of MRP in the Malpighian tubules, the functional equivalent to the human kidney, was sufficient to cause abnormal lipid accumulation and disrupt feeding behavior. Furthermore, reduced Malpighian tubule MRP expression resulted in increased Hr96 (homolog of human pregnane X receptor) expression. Hr96 is known to play a role in detoxification and lipid metabolism processes. Reduced expression of MRP in the Malpighian tubules also conveyed resistance to oxidative stress, as well as reduced normal levels of reactive oxygen species in adult flies. This study reveals that an evolutionarily conserved MRP is required in Drosophila Malpighian tubules for proper metabolic homeostasis.

Overexpression of ATP-binding cassette (ABC) transporters causing multidrug resistance (MDR) in cancer cells is one of the major obstacles in cancer chemotherapy. The 5-FU resistant subclone (HL-60/5FU) of the human HL-60 promyelocytic leukemia cell line was selected by the conventional method of continuous exposure of the cells to the drug up to 0.08 mmol/L concentration. HL-60/5FU cells exhibited six-fold enhanced resistance to 5-FU than HL-60 cells. RT-PCR and ELISA assay showed significant overexpression of MDR-related ABC transporters, ABCB1, ABCG2 but especially ABCC1 in the HL-60/5FU as compared with the parental cell line. Three novel synthetic 5-methylidenedihydrouracil analogs, U-236, U-332 and U-359, selected as highly cytotoxic for HL-60 cells in MTT test, showed similar cytotoxicity in the resistant cell line. When co-incubated with 5-FU, these analogs were found to down-regulate the expression of all three transporters. However, the most pronounced effect was caused by U-332 which almost completely abolished ABCC1 expression in the resistant HL-60/5FU cells. Additionally, U-332 inhibited the activity of ATPase, an enzyme which catalyzes hydrolysis of ATP, providing energy to efflux drugs from the cells through the cellular membranes. Taken together, the obtained data suggest that acquired 5-FU resistance in HL-60/5FU cells results from overexpression of ABCC1 and that targeting ABCC1 expression could be a potential approach to re-sensitize resistant leukemia cells to 5-FU. The synthetic uracil analog U-332, which can potently down-regulate ABC transporter expression and therefore disturb drug efflux, can be considered an efficient ABCC1 regulator in cancer cells. [ABSTRACT FROM AUTHOR]

Abstract Increasing evidence suggests that long non-coding RNAs (lncRNAs) are implicated with chemoresistance of cancers. However, their functional role and molecular mechanisms in colorectal cancer (CRC) chemoresistance are still largely unclear. In this work, we aimed to investigate the functional role of lncRNA cancer susceptibility candidate 15 (CASC15) in oxaliplatin (OXA) resistance of CRC and reveal the underlying molecular mechanism. Our results discovered that CASC15 was up-regulated in OXA-resistant CRC tissues and cells. Patients with high CASC15 expression level had a poor prognosis. CASC15 knockdown re-sensitized HT29/OXA and HCT116/OXA cells to OXA. Moreover, CASC15 could act as a competing endogenous RNA (ceRNA) to de-repress ABCC1 expression through sponging miR-145. miR-145 overexpression or ABCC1 knockdown could mimic the functional role of down-regulated CACS15 in OXA resistance, which was counteracted by CASC15 overexpression. Furthermore, CASC15 knockdown facilitated OXA sensitivity of OXA-resistant CRC cells in vivo. In summary, CASC15 silencing overcame OXA resistance of CRC by regulating miR-145/ABCC1 axis, providing a potential therapeutic target for CRC chemoresistance. [ABSTRACT FROM AUTHOR]