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Recent studies have shown that MDR could be induced by the high stemness of cancer cells. In a previous study, we found bufalin could reverse MDR and inhibit cancer cell stemness in colorectal cancer, but the relationship between them was unclear. Here we identified overexpressing CD133 increases levels of Akt/nuclear factor‐κB signaling mediators and MDR1, while increasing cell chemoresistance. Furthermore, bufalin reverses colorectal cancer MDR by regulating cancer cell stemness through the CD133/nuclear factor‐κB/MDR1 pathway in vitro and in vivo. Taken together, our results suggest that bufalin could be developed as a novel 2‐pronged drug that targets CD133 and MDR1 to eradicate MDR cells and could ultimately be combined with conventional chemotherapeutic agents to improve treatment outcomes for patients with colorectal cancer. Overexpressing CD133 increases levels of Akt/NF‐κB signaling mediators and MDR1. Bufalin reverses colorectal cancer multidrug resistance by regulating cancer cell stemness via the CD133/NF‐κB/MDR1 pathway.

Implementing the 3R initiative to reduce animal experiments in brain penetration prediction for CNS-targeting drugs requires more predictive in vitro and in silico models. However, animal studies are still indispensable to obtaining brain concentration and determining the prediction performance of in vitro models. To reveal species differences and provide reliable data for IVIVE, in vitro models are required. Systems overexpressing MDR1 and BCRP are widely used to predict BBB penetration, highlighting the impact of the in vitro system on predictive performance. In this study, endogenous Abcb1 knock-out MDCKII cells overexpressing MDR1 of human, mouse, rat or cynomolgus monkey origin were used. Good correlations between ERs of 83 drugs determined in each cell line suggest limited species specificities. All cell lines differentiated CNS-penetrating compounds based on ERs with high efficiency and sensitivity. The correlation between in vivo and predicted Kp,uu,brain was the highest using total ER of human MDR1 and BCRP and optimized scaling factors. MDR1 interactors were tested on all MDR1 orthologs using digoxin and quinidine as substrates. We found several examples of inhibition dependent on either substrate or transporter abundance. In summary, this assay system has the potential for early-stage brain penetration screening. IC50 comparison between orthologs is complex; correlation with transporter abundance data is not necessarily proportional and requires the understanding of modes of transporter inhibition.

[This corrects the article DOI: 10.3389/fvets.2025.1668282.].

Most patients who die of cancer have disseminated disease that has become resistant to multiple therapeutic modalities. Ample evidence suggests that the expression of ATP-binding cassette (ABC) transporters, especially the multidrug resistance protein 1 (MDR1, also known as P-glycoprotein or P-gp), which is encoded by ABC subfamily B member 1 (ABCB1), can confer resistance to cytotoxic and targeted chemotherapy. However, the development of MDR1 as a therapeutic target has been unsuccessful. At the time of its discovery, appropriate tools for the characterization and clinical development of MDR1 as a therapeutic target were lacking. Thirty years after the initial cloning and characterization of MDR1 and the implication of two additional ABC transporters, the multidrug resistance-associated protein 1 (MRP1; encoded by ABCC1)), and ABCG2, in multidrug resistance, interest in investigating these transporters as therapeutic targets has waned. However, with the emergence of new data and advanced techniques, we propose to re-evaluate whether these transporters play a clinical role in multidrug resistance. With this Opinion article, we present recent evidence indicating that it is time to revisit the investigation into the role of ABC transporters in efficient drug delivery in various cancer types and at the blood–brain barrier.

Isobavachalcone (IBC) is an active substance from the medicinal plant Psoralea corylifolia. This prenylated chalcone was reported to possess antioxidative, anti-inflammatory, antibacterial, and anticancer activities. Multidrug resistance (MDR) associated with the over-expression of the transporters of vast substrate specificity such as ABCB1 (P-glycoprotein) belongs to the main causes of cancer chemotherapy failure. The cytotoxic, MDR reversing, and ABCB1-inhibiting potency of isobavachalcone was studied in two cellular models: human colorectal adenocarcinoma HT29 cell line and its resistant counterpart HT29/Dx in which doxorubicin resistance was induced by prolonged drug treatment, and the variant of MDCK cells transfected with the human gene encoding ABCB1. Because MDR modulators are frequently membrane-active substances, the interaction of isobavachalcone with model phosphatidylcholine bilayers was studied by means of differential scanning calorimetry. Molecular modeling was employed to characterize the process of membrane permeation by isobavachalcone. IBC interacted with ABCB1 transporter, being a substrate and/or competitive inhibitor of ABCB1. Moreover, IBC intercalated into model membranes, significantly affecting the parameters of their main phospholipid phase transition. It was concluded that isobavachalcone interfered both with the lipid phase of cellular membrane and with ABCB1 transporter, and for this reason, its activity in MDR cancer cells was presumptively beneficial.

Z inc c luster transcription f actors (Zcfs) encoding zcf genes are exclusive for fungi and required for multiple cellular processes including metabolism and development. Genome-wide screening of 228 zinc cluster transcription factor encoding genes by overexpression in Aspergillus fumigatus revealed 11 genes which provided increased tolerance to the broadly applied azole voriconazole or to the polyene amphotericin B or to both. These include four o xidative stress and d rug r esistance genes ( odrA-D ) genes encoding factors, which provide broad cellular stress protection. Thereby, the corresponding fungal OdrA/Mdu2- and AtrR/OdrD-dependent genetic networks are interconnected. OdrA/Mdu2 activates atrR / odrD transcription by direct binding to the promoter, whereas AtrR/OdrD functions as repressor of odrA / mdu2 expression. odrA / mdu2 overexpression provides combined resistance to amphotericin B, voriconazole, itraconazole, and reactive oxygen species generated by menadione. OdrA/Mdu2-mediated itraconazole resistance is evoked by direct regulation of the transporter encoding gene mdr1 . Oxidative stress-inducing substances like amphotericin B and menadione promote OdrA/Mdu2 accumulation in the nucleus to regulate stress response genes like mdr1 and the putative glutathione-S-transferase encoding gene gstD . The expression levels and external stress conditions fostering nuclear accumulation of OdrA/Mdu2 determine the regulation of the target genes. Hence, OdrA/Mdu2 provides a combined adaptation strategy for survival in nature or within a potential host, where this fungus represents the most common agent for human mold pneumonia worldwide. The OdrA/Mdu2 controlled genetic network highlights the tight connection between oxidative stress response and antifungal drug adaption to secure A. fumigatus survival in various hostile environments. An overexpression screen of 228 zinc cluster transcription factor encoding genes of A. fumigatus revealed 11 genes conferring increased tolerance to antifungal drugs. Out of these, four oxidative stress and drug tolerance transcription factor encoding odr genes increased tolerance to oxidative stress and antifungal drugs when overexpressed. This supports a correlation between oxidative stress response and antifungal drug tolerance in A. fumigatus . OdrA/Mdu2 is required for the cross-tolerance between azoles, polyenes, and oxidative stress and activates genes for detoxification. Under oxidative stress conditions or when overexpressed, OdrA/Mdu2 accumulates in the nucleus and activates detoxifying genes by direct binding at their promoters, as we describe with the mdr1 gene encoding an itraconazole specific efflux pump. Finally, this work gives new insights about drug and stress resistance in the opportunistic pathogenic fungus A. fumigatus .

Purpose All patients with metastatic breast cancer (MBC) expressing estrogen receptor-α (ESR1) will eventually develop resistance to endocrine therapies. In up to 40% of patients, this resistance is caused by activating mutations in the ligand-binding domain (LBD) of ESR1. Accumulating clinical evidence indicate adverse outcomes for these patients, beyond that expected by resistance to endocrine therapy. Here we aimed to study the role of ESR1 mutations in conferring chemoresistance in BC cells. Methods MCF-7 cells harboring Y537S and D538G ESR1 mutations (mut-ER) were employed to study the response to chemotherapy drugs, paclitaxel and doxorubicin, using viability and apoptotic assay in vitro, and tumor growth in vivo. JNK/c-Jun/MDR1 pathway was studied using qRT-PCR, western-blot, gene-reporter and ChIP assays. MDR1 expression was analyzed in clinical samples using IHC. Results  Cell harboring ESR1 mutations displayed relative chemoresistance compared to WT-ER, evidenced by higher viability and reduced apoptosis as well as resistance to paclitaxel in vivo. To elucidate the underlying mechanism, MDR1 expression was examined and elevated levels were observed in mut-ER cells, and in clinical BC samples. MDR1 is regulated by the c-Jun pathway, and we showed high correlation between these two genes in BC using TCGA databases. Accordingly, we detected higher JNK/c-Jun expression and activity in ESR1-mutated cells, as well as increased occupancy of c-Jun in MDR1 promoter. Importantly, JNK inhibition decreased MDR1 expression and restored sensitivity to chemotherapy. Conclusions Taken together, these data indicate that ESR1 mutations confer chemoresistance through activation of the JNK/MDR1 axis. These finding suggest a novel treatment option for BC tumors expressing ESR1 mutations.

This study examined the effects of chitosan nanoparticles (CS-NPs) loaded with ribavirin (CS-R-NPs), carboplatin (CS-C-NPs), and Thymus vulgaris essential oil (CS-TV-NPs) on gene expression in Candida glabrata and Candida tropicalis . C. glabrata and C. tropicalis strains were obtained from Tarbiat Modares University. CS-NPs were synthesized via the ionic gelation method and characterized through dynamic light scattering, electrophoretic light scattering and transmission electron microscopy. Cytotoxicity was assessed via the MTT assay in fibroblasts. The minimum inhibitory concentrations (MICs) of the nanoparticle-encapsulated formulations were determined via the microdilution method per the CLSI-M27-A3/S4 guidelines. The gene expression of SNQ2 and ERG11 in C. glabrata and that of CDR1 and MDR1 in C. tropicalis was quantified via qRT‒PCR. CS-R-NPs, CS-C-NPs and CS-TV-NPs demonstrated high encapsulation efficiencies (81–91%), hydrodynamic diameters of approximately 286–298 nm, and positive zeta potentials (+ 33 to + 34 mV), with a spherical morphology and minimal aggregation. In vitro drug release extended over 64 h, with CS-TV-NPs achieving the highest cumulative release (60%). Cytotoxicity assays indicated that the CS-TV-NPs presented the highest IC50 (20.31 µg/ml). Compared with free drugs, encapsulated formulations significantly lowered the MIC values against C. glabrata and C. tropicalis , enhancing antifungal efficacy. qRT‒PCR confirmed notable downregulation of SNQ2 and ERG11 in C. glabrata and of CDR1 and MDR1 in C. tropicalis , with the most pronounced effects observed in the CS-NP-treated groups. CS-NPs significantly enhanced antifungal efficacy by reducing MIC values and downregulating resistance genes, highlighting their potential as effective drug delivery systems against Candida infections.

P53 mutation is an important cause of chemoresistance in colorectal cancer (CRC). The investigation and identification of the downstream targets and underlying molecular mechanism of chemoresistance induced by P53 abnormalities are therefore of great clinical significance. In this study, we demonstrated and reported for the first time that leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) is a key functional downstream factor and therapeutic target for P53 mutation-induced chemoresistance. Due to its RNA binding function, LRPPRC specifically bound to the mRNA of multidrug resistance 1 (MDR1), increasing MDR1 mRNA stability and protein expression. In normal cells, P53 induced by chemotherapy inhibited the expression of LRPPRC via miR-34a and in turn reduced the expression of MDR1. However, chemotherapy-induced P53/miR-34a/LRPPRC/MDR1 signalling pathway activation was lost when P53 was mutated. Additionally, the accumulated LRPPRC and MDR1 promoted drug resistance. Most importantly, gossypol-acetic acid (GAA) was recently reported by our team as the first specific inhibitor of LRPPRC. In CRC cells with P53 mutation, GAA effectively induced degradation of the LRPPRC protein and reduced chemoresistance. Both in vivo and in vitro experiments revealed that combination chemotherapy with GAA and 5-fluorouracil (5FU) yielded improved treatment outcomes. In this study, we reported a novel mechanism and target related to P53-induced drug resistance and provided corresponding interventional strategies for the precision treatment of CRC.

A 4‐base pair deletion in the ABCB1 (MDR1) gene, resulting in a frameshift and truncated, nonfunctional P‐glycoprotein, is frequently observed in certain dog breeds and is known to cause drug sensitivity. Another variant, a single nucleotide substitution (c.‐6‐180T > G) located near the gene’s promoter region, has also been identified; however, its clinical significance remains unclear. This study aimed to determine the genotype distribution of the nt230(del4) deletion and the c.‐6‐180T > G substitution across various dog breeds and to evaluate whether an association exists between these variants. A total of 263 client‐owned dogs from 17 breeds were genotyped for both mutations. Genomic DNA was extracted using a spin column–based method. The deletion was detected using a modified allele‐specific real‐time PCR assay, and the SNP was assessed via PCR followed by RFLP analysis. The nt230(del4) mutation was identified exclusively in collie‐lineage breeds, including collie, Shetland sheepdog, Australian shepherd, bobtail, and white Swiss shepherd. The c.‐6‐180T > G SNP was widespread across all breeds, with a G allele frequency of 35%. Genotype distribution included 111 T/T homozygotes, 119 T/G heterozygotes, and 33 G/G homozygotes. Notably, all individuals carrying the deletion also possessed at least one G allele, suggesting a co‐occurrence between the two variants. The observed association between the nt230(del4) deletion and the c.‐6‐180T > G SNP in this cohort may reflect shared ancestry and/or local linkage disequilibrium. Further research is warranted to explore the functional consequences of this SNP and its potential role in canine drug response.