Search Results (106)

Beneficial effects of the microbiota-derived metabolite butyrate at the colonic level are well established, particularly through its relevance in colorectal cancer (CRC) and inflammatory bowel disease (IBD), two major intestinal pathologies. Therefore, the mechanisms involved in butyrate transport across colonic epithelial cell membranes (uptake transporters: monocarboxylate transporter 1 (MCT1) and sodium-coupled monocarboxylate transporter 1 (SMCT1); efflux transporters: breast cancer resistance protein (BCRP) and MCT1/monocarboxylate transporter 4 (MCT4)), which are determinant for its intracellular levels, are of primary importance for its beneficial effects at the colonic level. The available data suggest that all these butyrate transporters can be modulated by redox and inflammatory status, but the evidence is scarce and rather inconsistent. Nevertheless, a role of nuclear factor erythroid 2-related factor 2 (Nrf2) and of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in mediating the effect of oxidative stress and inflammation, respectively, on MCT1 and SMCT1 is suggested. So, more investigation on this subject is needed, given the fact that increased oxidative stress levels and inflammatory status are present in a series of intestinal conditions and pathologies, including CRC and IBD, which could help to establish these transporters as potential cellular targets in these diseases. Full article

P-glycoprotein (P-gp) is an ATP-driven transporter that effluxes a wide range of xenobiotics from cells, and its overexpression is a primary cause of multidrug resistance (MDR) in cancer. It is well-established that P-gp functions through conformational changes, yet its large-scale structural dynamics at work have been unexplored. Here, we directly visualized single P-gp molecules reconstituted in nanodiscs using high-speed atomic force microscopy (HS-AFM). The HS-AFM movies revealed that P-gp is intrinsically dynamic in its apo state, with its nucleotide-binding domains (NBDs) undergoing large, spontaneous opening and closing motions. However, addition of ATP stabilized a conformation characterized by NBD proximity with a strong tendency toward closure. We then leveraged this dynamic viewpoint to elucidate the relationship between Elacridar’s function and the resulting structural dynamics of P-gp. Elacridar is designed to overcome multidrug resistance (MDR) in cancer and acts as a potent dual inhibitor of both P-gp and the Breast Cancer Resistance Protein (BCRP), effectively blocking the drug efflux function of these transporters. This inhibitor has suggested concentration-dependent function: it is effluxed as a substrate at low concentrations and acts as an inhibitor at high concentrations. Our direct observations revealed that low concentrations induced active dynamics in P-gp, whereas high concentrations severely restricted its motion, leading to a rigid, non-productive state. Our study provides critical insights into how observing molecular motion itself can unravel complex biological mechanisms. Full article

Multidrug resistance (MDR) remains a major obstacle in the treatment of ovarian cancer. MDR is often mediated by the overexpression of ATP-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). In this study, we evaluated the ability of elacridar, a dual P-gp and BCRP inhibitor, to overcome MDR in W1, an ovarian cancer cell line sensitive to Paclitaxel (PAC) and its PAC-resistant variants. Cells were cultured under both two-dimensional (2D) and three-dimensional (3D) conditions to account for differences in tumor-like microenvironments. The MDR1 gene and P-gp protein expression were determined for the analyzed model; P-gp activity was measured by flow-cytometry and fluorescent observation, with and without elacridar. The MTT tests were carried out to evaluate how elacridar, combined with chemotherapeutics, affects cell viability. Our results demonstrate that elacridar effectively inhibited transporter activity and increased cellular sensitivity to PAC and DOX. The inhibitory effect was observed in both 2D and 3D cultures, although the re-sensitization effect in 3D conditions was less pronounced, reflecting the complexity of tumor-specific resistance mechanisms. These findings highlight elacridar as a promising compound for reversing MDR in ovarian cancer and emphasize the importance of 3D models in preclinical drug evaluation. Further studies in advanced in vitro and in vivo models are required to assess the potential of elacridar better. Full article

Gut microbiota, through both its species composition and its metabolites, impacts expression and activity of intestinal drug transporters. This phenomenon directly affects absorption process of orally administered drugs and contributes to the observed inter-individual variability in pharmacotherapeutic responses. This review summarizes mechanistic evidence from in vitro and animal studies and integrates clinical observations in which alterations in gut microbiota are associated with changes in oral drug exposure, consistent with potential regulation of key intestinal drug transporters—such as P-glycoprotein (P-gp, ABCB1), Breast Cancer Resistance Protein (BCRP, ABCG2), MRP2/3 proteins (ABCC2/3), and selected Organic Anion-Transporting Polypeptides (OATPs, e.g., SLCO1A2, SLCO2B1)—by major bacterial metabolites including short-chain fatty acids (SCFAs), secondary bile acids, and tryptophan-derived indoles. The molecular mechanisms involved include activation of nuclear and membrane receptors (PXR, FXR, AhR, TGR5), modulation of transcriptional and stress-response pathways (Nrf2, AP-1) with simultaneous suppression of pro-inflammatory pathways (NF-κB), and post-translational modifications (e.g., direct inhibition of P-gp ATPase activity by Eggerthella lenta metabolites). The review also highlights the pharmacokinetic implications of, e.g., tacrolimus, digoxin, and metformin. In conclusion, the significance of “drug–transporter–microbiome” interactions for personalized medicine is discussed. Potential therapeutic interventions are also covered (diet, pre-/probiotics, fecal microbiota transplantation, modulation of PXR/FXR/AhR pathways). Considering the microbiota as a “second genome” enables more accurate prediction of drug exposure, reduction in toxicity, and optimization of dosing for orally administered preparations. Full article

The active efflux of drugs by adenosine triphosphate (ATP)-binding cassette (ABC) trans-porters, such as multidrug resistance protein 1 (MDR1/ABCB1), multidrug resistance-associated protein 1 and 2 (MRP1/ABCC1; MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2), is a well-established mechanism contributing to multidrug resistance (MDR). Interestingly, various vitamin A-based molecules have been found to influence the expression or function of these transporters. This work investigated the current evidence on the effects of retinoids, rexinoids, and carotenoids on ABC transporters and their potential to reverse MDR. Several studies indicated that these compounds could inhibit ABC transporter activity at non-toxic concentrations, either by downregulating gene/protein expression or by directly blocking efflux function. These effects were often associated with increased chemosensitivity to several conventional anticancer agents. Overall, the degree of inhibition varied depending on several factors, including compound type and their chemical modification, dose, incubation time, treatment timing, the type of target cells, method of transporter overexpression, and coadministration with other compounds. Although particular attention was paid to elucidating the underlying mechanisms, current knowledge in this area remains limited. Moreover, extensive in vivo and clinical studies validating these findings are still lacking, emphasizing the need for further research to evaluate their translational potential. Full article

Background/Objectives: Ochratoxin A (OTA) is a widespread foodborne mycotoxin linked to chronic kidney disease of unknown etiology. Despite evidence from animal models showing OTA accumulation in the kidney, the molecular mechanisms underlying its renal disposition in humans remain only partially understood. Here, we identify human renal transporters responsible for OTA kidney accumulation, elimination, and establish Michaelis–Menten kinetics under matched conditions to directly compare transport mechanisms. We also aim to identify inhibition potential of these transport mechanisms with common dietary polyphenols. Methods: Mammalian cells and membrane vesicles overexpressing human renal transporters were used to screen and profile the uptake and efflux of OTA. Miquelianin, (-)-Epicatechin-3-O-gallate, myricetin, luteolin, and caffeic acid were tested as potential concentration-dependent transporter inhibitors. Results: We demonstrate that OTA is a substrate for human organic anion transporter (hOAT) 1 (K_m: 2.10 ± 0.50 μM, V_max: 396.9 ± 27.0 pmol/mg/min), hOAT3 (K_m: 2.58 ± 0.83 μM, V_max: 141.4 ± 30.3 pmol/mg/min), hOAT4 (K_m: 6.38 ± 1.45 μM, V_max: 96.9 ± 18.8 pmol/mg/min), and human organic anion transporting polypeptide (hOATP) 1A2 (K_m: 37.3 ± 6.2 μM, V_max: 801.0 ± 133.9 pmol/mg/min). Among efflux transporters, OTA was transported only by human breast cancer resistance protein (hBCRP), which has minimal renal expression. While none of the uptake transporters were potently inhibited (>90%) by polyphenols at 10 μM, luteolin inhibited hBCRP-mediated transport of OTA with an IC₅₀ of 22 μM and caffeic acid stimulated hBCRP-mediated efflux with an EC₅₀ of 713.8 μM, both of which are physiologically relevant intestinal lumen concentrations. Conclusions: Our results confirm that exposure to OTA will lead to renal accumulation and increased health risks in affected populations, necessitating increased scrutiny of our food sources. Full article

Background/Objectives: Polygoni Cuspidati Rhizoma et Radix (PCRR) is an herb and a source of a resveratrol-containing dietary supplement. Breast cancer resistance protein (BCRP) is an ATP-binding cassette transporter involved in numerous drug-related pharmacokinetic interactions. This study used both in vivo and in vitro models to investigate the modulation effect of PCRR ingestion on BCRP. Methods: Three groups of rats were orally administered methotrexate (MTX), a probe substrate of BCRP, without and with PCRR at 1.0 g/kg and 2.0 g/kg in a parallel design, and the MTX pharmacokinetics were compared among three treatments. The modulation effects of PCRR and its serum metabolites (PCRRM) on BCRP were assayed by in vitro models. Results: PCRR at 1.0 g/kg and 2.0 g/kg significantly decreased the area under the serum level–time curve from 0 to 240 min (AUC_0-240) of MTX by 31% and 58%, respectively; 2.0 g/kg of PCRR markedly increased the area under the serum level–time curve from 240 to 2880 min (AUC_240-2880) and the mean residence time (MRT) of MTX by 39% and 74%, respectively. The results of in vitro assays indicated that PCRR enhanced the function of BCRP by 33~48%; on the contrary, PCRRM reduced the function of BCRP by 200~209%. Conclusions: PCRR activated BCRP, whereas PCRRM inhibited BCRP, thereby the coadministration of PCRR reduced both the absorption and excretion of MTX in rats. In clinical practice, the concurrent use of PCRR with critical BCRP substrate drugs should be avoided. Full article

Background: Asciminib (Scemblix^®) is approved for the first-line treatment of adult patients with chronic myeloid leukemia in the chronic phase at 40 mg twice daily (BID) and 80 mg once daily (QD) or 200 mg BID for patients harboring the T315I mutation. Objectives: (1) Extrapolate the DDI magnitude as the perpetrator or victim of other drugs and the effect of organ impairment to untested doses; (2) Predict clinically untested DDI scenarios. Methods: Asciminib is primarily cleared by cytochrome P450 (CYP)3A4, UDP-glucuronosyltransferases (UGT)2B7, UGT2B17, UGT1A3/4, and the breast-cancer-resistance protein (BCRP). In vitro asciminib is an inhibitor of several CYP, UGT enzymes, and transporters and is an inducer of CYP1A2 and CYP3A4. Clinical DDI studies assessed asciminib 40 mg BID as a perpetrator on CYP-sensitive substrates. Additional studies evaluated the impact of strong CYP3A4 perpetrators and imatinib on a single 40 mg dose of asciminib. Hepatic and renal impairment studies were also conducted at the 40 mg dose. A nonlinear whole-body physiologically based pharmacokinetic (PBPK) model was developed and verified for asciminib as a CYP3A4, UGT, and BCRP substrate and a perpetrator of several CYP and UGT enzymes. Results: This PBPK model was applied in lieu of clinical pharmacology studies to support the new drug application of Scemblix^® and to bridge data from 40 mg BID to the 80 mg QD and 200 mg BID dose regimens. Conclusions: The PBPK predictions informed the drug product label and are estimated to have replaced at least 10 clinical studies. Full article

Background: Baicalin (BG) has been used in the treatment of many diseases. However, the effect of hepatic insufficiency on its pharmacokinetics has not been reported, and there is a lack of clinical guidance for the use of BG in patients with hepatic impairment. Methods: Carbon tetrachloride (CCl₄)-induced rat models were used to simulate hepatic failure patients to assess the effect of hepatic impairment on the pharmacokinetics and distribution of BG. In vitro metabolism and transporter studies were employed to elucidate the potential mechanisms. Results: After intragastric administration of 10 mg/kg of BG, the peak plasma concentration and exposure (AUC_0–t) of BG decreased by 64.6% and 52.6%, respectively, in CCl₄-induced rats. After intravenous administration, the AUC_0–t decreased by 73.6%, and unlike in the control group, the second absorption peak of BG was not obvious in the concentration–time curve of CCl₄-induced rats. The cumulative excretion of BG in the feces increased, but that in the bile decreased. In vivo data indicated that the absorption and enterohepatic circulation of BG were affected. In vitro studies found that the hydrolysis of BG to the aglycone baicalein decreased significantly in the intestinal tissues and contents of the CCl₄-induced rats. And BG was identified as a substrate for multiple efflux and uptake transporters, such as breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs), organic anion transporting polypeptides (OATP1B1, 1B3, 2B1), and organic anion transporters (OATs). The bile acids accumulated by liver injury inhibited the uptake of BG by OATPs, especially that by OATP2B1. Conclusions: Hepatic impairment reduced BG hydrolysis by intestinal microflora and inhibited its transporter-mediated biliary excretion, which synergistically led to the attenuation of the enterohepatic circulation of BG, which altered its pharmacokinetics. Full article

Chemotherapy resistance is a major obstacle in the treatment of ovarian cancer, often resulting in disease recurrence and poor prognosis for patients. A key contributor to this resistance is the overexpression of ATP-binding cassette (ABC) transporters, including breast cancer resistance protein (BCRP/ABCG2), which actively effluxes chemotherapeutic agents such as topotecan (TOP) or mitoxantrone (MIT), limiting their intracellular accumulation and efficacy. This study investigated the potential of elacridar (GG918), a potent dual P-gp and BCRP inhibitor, to overcome drug resistance in ovarian cancer cell lines. Both TOP-sensitive and TOP-resistant ovarian cancer cells were grown in two-dimensional (2D) monolayers and three-dimensional (3D) spheroid models to better mimic the tumor microenvironment. The expression of the ABCG2 gene was quantified via qPCR and BCRP protein levels were assessed by western blotting and immunofluorescence. Drug response was evaluated using MTT viability assays, while BCRP transporter activity was examined using flow cytometry and microscopic assessment of the intracellular retention of BCRP fluorescent substrates (Hoechst 33342 and MIT). In both 2D and 3D cultures, elacridar effectively inhibited BCRP function and significantly enhanced sensitivity to TOP. These findings suggest that elacridar can inhibit BCRP-mediated drug resistance in ovarian cancer cell models. Full article

Breast milk provides significant health benefits to both infants and mothers, offering protection against infections and enhancing cognitive development. This paper examines the complex effects of substance use disorder (SUD) during pregnancy and lactation, focusing on the pharmacokinetics of drug transfer into breast milk. It highlights the mechanisms by which drugs enter milk, emphasizing the roles of passive diffusion and active transport, particularly through breast cancer resistance protein (BCRP). The study explores the impact of various substances on fetal and infant health, with a focus on the relative infant dose (RID) and milk-to-plasma (MP) ratio as key metrics for assessing drug safety in breastfeeding. The findings underscore the need for careful evaluation of maternal drug use during lactation to balance the benefits of breastfeeding with potential risks. Full article

Chemotherapy resistance, particularly multidrug resistance (MDR), remains a significant barrier to effective cancer treatment, leading to high mortality rates. The development of novel therapeutic strategies targeting key molecular mechanisms to counteract drug resistance is thus an urgent clinical need. In this study, we evaluated the potential of the small molecule SCO-101 to restore chemotherapy sensitivity in drug-resistant cancer cells. Using in silico and in vitro models such as molecular docking, cell viability, colony formation, dye efflux, transporter assays and chemotherapy retention, we assessed the impact of SCO-101 on drug retention and response in several drug-resistant cancer cells. SCO-101 was found to inhibit the activity of breast cancer resistance protein (BCRP/ABCG2) and UDP Glucuronosyltransferase Family 1 Member A1 (UGT1A1), two key proteins involved in drug resistance by cellular drug excretion and drug metabolism. Our results demonstrate that inhibition of these proteins by SCO-101 leads to increased intracellular drug accumulation, enhancing the cytotoxic effects of chemotherapy agents. Additionally, we identified a strong correlation between high ABCG2 expression and MDR in non-drug-resistant models, where cells exhibiting elevated ABCG2 levels displayed chemotherapy resistance, which was effectively reversed by SCO-101 co-treatment. These findings highlight the therapeutic potential of SCO-101 in overcoming MDR by inhibiting drug efflux mechanisms and metabolism, thereby enhancing chemotherapy efficacy. SCO-101 is currently undergoing clinical trials as an orally administered drug and is considered a promising strategy for improving cancer treatment outcomes in patients with drug-resistant tumors. Full article

Background/Objectives: The increasing use of statins in people with cystic fibrosis (CF) necessitates the investigation of potential drug–drug interactions (DDI) of statins with cystic fibrosis transmembrane conductance regulator (CFTR) modulators, including elexacaftor, tezacaftor, and ivacaftor (ETI). The interactions may involve the potential inhibition of cytochrome P450 isoenzymes (CYPs), organic anion-transporting polypeptides (OATPs), and Breast Cancer Resistance Protein (BCRP) by ETI. This presents a therapeutic challenge in CF due to the potential for elevated statin levels, consequently heightening the risk of myopathy. This study aimed to predict potential DDIs between statins and ETI using a physiologically based pharmacokinetic (PBPK) modeling approach. Methods: We performed in vitro assays to measure the inhibitory potency of ETI against OATPs and CYP2C9 and incorporated these data into our PBPK models alongside published inhibitory parameters for BCRP and CYP3A4. Results: The PBPK simulation showed that atorvastatin had the highest predicted AUC ratio (3.27), followed by pravastatin (2.27), pitavastatin (2.24), and rosuvastatin (1.83). Conclusions: Based on these findings, rosuvastatin appears to exhibit a weak interaction with ETI, whereas other statins exhibited a moderate interaction, potentially requiring appropriate dose reductions. These data indicate potential clinically significant DDIs between ETI and certain statins, which warrants a clinical study to validate these findings. Full article

Multidrug resistance (MDR) development against cytotoxic drugs by tumor cells is one of the main causes of treatment failure in gastrointestinal cancers, a group of cancers of great relevance due to their prevalence and/or mortality. This phenomenon is mediated by diverse mechanisms, including the overexpression of members of the superfamily of membrane transporters of the ATP-binding cassette (ABC). Most of these molecules, including P-glycoprotein (P-gp or MDR1/ABCB), MDR-associated protein 1 (MRP1/ABCC1), MRP2, and breast cancer resistance protein (BCRP/ABCG2), are integrated in the cell membrane, acting as drug efflux pumps. Despite the use of various MDR modulators as adjuvants to improve the chemotherapy response, the results have not been satisfactory. Natural products from plants, such as flavonoids, alkaloids, terpenoids, and coumarins, are capable of modifying drug resistance, suggesting an improvement in the antitumoral effect of the current treatments without generating side effects. This review aims to provide an overview of the most recent studies in relation to plant-derived molecules and extracts that modulate resistance to antitumor drugs and that could be applied in the future in clinical practice to improve the treatment of patients with gastrointestinal cancer. Full article

Acquired resistance to chemotherapeutic drugs is the primary cause of treatment failure in the clinic. While multiple factors contribute to this resistance, increased expression of ABC transporters—such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance proteins—play significant roles in the development of resistance to various chemotherapeutics. We found that Erastin, a ferroptosis inducer, was significantly cytotoxic to NCI/ADR-RES, a P-gp-expressing human ovarian cancer cell line. Here, we examined the effects of both Erastin and RSL3 (Ras-Selected Ligand 3) on reversing Adriamycin resistance in these cell lines. Our results show that Erastin significantly enhanced Adriamycin uptake in NCI/ADR-RES cells without affecting sensitive cells. Furthermore, we observed that Erastin enhanced Adriamycin cytotoxicity in a time-dependent manner. The selective iNOS inhibitor, 1400W, reduced both uptake and cytotoxicity of Adriamycin in P-gp-expressing NCI/ADR-RES cells only. These findings were also confirmed in a BCRP-expressing human breast cancer cell line (MCF-7/MXR), which was selected for resistance to Mitoxantrone. Both Erastin and RSL3 were found to be cytotoxic to MCF-7/MXR cells. Erastin significantly enhanced the uptake of Hoechst dye, a well-characterized BCRP substrate, sensitizing MCF-7/MXR cells to Topotecan. The effect of Erastin was inhibited by 1400W, indicating that iNOS is involved in Erastin-mediated enhancement of Topotecan cytotoxicity. RSL3 also significantly increased Topotecan cytotoxicity. Our findings—demonstrating increased cytotoxicity of Adriamycin and Topotecan in P-gp- and BCRP-expressing cells—suggest that ferroptosis inducers may be highly valuable in combination with other chemotherapeutics to manage patients’ cancer burden in the clinical setting. Full article