Amdray (valspodar) / Novartis - LARVOL DELTA

Advanced kidney models to better understand tacrolimus-induced nephrotoxicity (ERA 2025) - "Cells were exposed for 24 hours to tacrolimus (16 µM-104 µM), with and without the addition of the P-gp inhibitor, PSC-833... Our results indicate that proximal tubule kidney cells respond differently to tacrolimus compared to distal cells. Future research will focus on the compensatory mechanisms in distal tubules and ABCB1 mutant organoids as well as identifying the initiating pathways of tacrolimus-induced nephrotoxicity. Advanced in vitro kidney models combined with the AOP framework offer a novel method for understanding tacrolimus-induced nephrotoxicity."

Metastases • Fibrosis • Immunology • Metabolic Disorders • Nephrology • Solid Organ Transplantation • ABCB1 • KIM1 • LCN2 • TGFB1

Clarification and overcoming the resistance mechanisms to inotuzumab ozogamicin and ponatinib in B-ALL (AACR 2025) - "The combination of IO and a p-gp inhibitor, PSC-833, decreased the IC50 values of IO by 90% and increased apoptosis...When combined with IO and PARP inhibitors, olaparib and talazoparib, increased the IO sensitivity of resistant cell lines by 50 to 90%...DNA microarray showed that JAK2 expression was upregulated in resistant cell line.[Conclusion] The present study indicated that inhibition of drug efflux and DNA damage repair overcame the resistance to IO in Ph-negative B-ALL. Moreover, JAK2 might be the therapeutic target to overcome the resistance to ponatinib in Ph-positive B-ALL."

Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • ABCB1 • JAK2

Biased Equilibrium Drives Cyclosporine Membrane Permeability: The Goldilocks Energy Barriers. (PubMed, J Med Chem) - "Conformational flexibility allows macrocyclic peptides like cyclosporine A (CycA) to cross membranes, yet drug design leveraging this property has largely failed. This mechanism explains why CycH, Valspodar (VALSPO), and O-acetyl CycA (OAc-CycA) fail to cross membranes─they adopt similar states but lack this biased equilibrium. Our findings provide a new strategy for designing membrane-permeable N-methylated macrocycles and underscore the role of high-energy conformers as transition states between membrane permeability and target engagement─offering critical insights for drug development."

Journal

Scutellarein enhances cisplatin‑induced apoptotic effects by suppressing the PI3K/AKT‑MDR1 pathway in human NPC/HK1 nasopharyngeal carcinoma cells. (PubMed, Biomed Rep) - "AKT phosphorylation and MDR1 expression triggered by cisplatin were inhibited by treatment with LY294002, a PI3K/AKT inhibitor. Moreover, treatment with the MDR1 inhibitor, PSC833, inhibited MDR1 expression and increased the cisplatin-induced viability inhibition and cytokeratin 18 fragment release. These findings indicated that scutellarein enhances the anticancer effects of cisplatin by inhibiting the PI3K/AKT-MDR1 signaling pathway in NPC/HK1 cells."

Journal • Nasopharyngeal Carcinoma • Oncology • Solid Tumor • ABCB1 • ABCC1 • ATG3 • BECN1 • CASP7 • CASP8 • KRT18

Screening of photosensitizers-ATP binding cassette (ABC) transporter interactions in vitro. (PubMed, Cancer Drug Resist) - " The ABCG2 inhibitor (fumitremorgin C) and P-gp inhibitor (valspodar) effectively blocked the transport mediated by ABCG2 and P-gp of rose bengal and BPD... In summary, our study provided new knowledge that temoporfin, talaporfin sodium, methylene blue, and indocyanine green are not substrates of ABCG2, P-gp, or MRP1...Rose bengal is a substrate of ABCG2, P-gp, and MRP1. The results presented here indicate ABC transporter substrate status as a possible cause for cellular resistance to photodynamic therapy with rose bengal, redaporfin, and BPD."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • ABCB1 • ABCC1 • ABCG2

Potency and mechanism of p-glycoprotein chemosensitizers in rainbow trout (Oncorhynchus mykiss) hepatocytes. (PubMed, Fish Physiol Biochem) - "The effects of four known mammalian chemosensitizers (cyclosporin A [CsA], quinidine, valspodar [PSC833], and verapamil) on the P-gp-mediated transport of rhodamine 123 (R123) and cortisol in primary cultures of rainbow trout (Oncorhynchus mykiss) hepatocytes were examined. In an ATP depletion assay, hepatocytes incubated with all four chemosensitizers resulted in lower free ATP concentrations, suggesting that they act via competitive inhibition. Chemosensitizers that inhibit MXR transporters are an important class of environmental pollutant, and these results show that rainbow trout transporters are inhibited by similar chemosensitizers (and mostly at similar concentrations) as seen in mammals and other fish species."

Journal • ABCB1

Establishment of Inotuzumab ozogamicin resistant leukemia cell lines; Focusing on p-gp and DNA damage repair for overcoming drug resistance (AACR 2024) - "Reh cells were synergistically sensitized to IO by the addition of non-toxic concentrations of PARP inhibitors, olaparib or talazoparib, with the Combination Index of 0.19 and 0.42, respectively. The present study demonstrated that the combination of IO with PARP inhibitors exerted synergistic cytotoxicity via the inhibition of DNA repair. In addition, it was suggested that overexpression of p-gp caused IO resistance, which was partially reversed with the combination of PARP inhibitors or a p-gp inhibitor."

Preclinical • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • ABCB1

Effect of Apolipoprotein E isoforms on the Abundance and Function of P-glycoprotein in Human Brain Microvascular Endothelial Cells. (PubMed, Pharm Res) - "Different apoE isoforms have no direct influence on P-gp abundance or function within this model, and further in vivo studies would be required to address whether P-gp abundance or function are reduced in sporadic AD in an apoE isoform-specific manner."

Journal • Alzheimer's Disease • CNS Disorders • APOE

Assessment of P-Glycoprotein Function Using Canine Intestinal Organoid-Derived Epithelial Interfaces. (PubMed, Xenobiotica) - "Dspite this disparity in gene expression, the transport activity of P-gp, as assessed by the efflux of Rhodamine 123 and Doxorubicin with PSC833 inhibition, did not exhibit significant differences between these two time points.Canine intestinal organoid-derived monolayers provide a valuable tool for investigating P-gp-mediated drug transport. These findings highlight the potential for predicting drug bioavailability and adverse reactions in veterinary medicine, aligning with principles of ethical and sustainable research."

Journal • ABCB1

Development and Functional Evaluation of MDR1-Expressing Microvascular Endothelial-Like Cells Derived from Human iPS Cells as an In Vitro Blood-Brain Barrier Model. (PubMed, J Pharm Sci) - "The basolateral-to-apical transport of MDR1 substrates, such as quinidine, [H]digoxin and [H]vinblastine, was higher than the apical-to-basolateral transport, and the efflux-dominant transport was attenuated by PSC833, an MDR1-specific inhibitor, indicating that MDR1-mediated efflux transport is functional. The robust MDR1 function was also supported by the efflux-dominant transports of [H]cyclosporin A, loperamide, cetirizine, and verapamil by MDR1-expressing hiPS-BMECs. These results suggest that MDR1-expressing hiPS-BMECs can be used as an in vitro model of the human BBB."

Journal • Preclinical • ABCB1

Comparative study on ABCB1-dependent efflux of anthracyclines and their metabolites: consequences for cancer resistance. (PubMed, Xenobiotica) - No abstract available

Journal • Oncology • ABCB1

Renal ABCA1 Deficiency Induces TLR4 that Regulates Epithelial Sodium Channel (ENaC) (KIDNEY WEEK 2023) - "We hypothesize that TLR4 contributes to cation transport in an ABCA1 deficient model. Transgenic mice, which express a doxycycline inducible CRE in tubules, were bred with mice expressing floxed ABCA1 to produce mice deficient in ABCA1 (FF)...Immunofluorescence (IF) was performed on kidneys and amiloride sensitive short-circuit current (AIsc) measured in mpkCCD cells. Mice were fed a 1% chol diet (X 6 weeks), a low Na and a high Na diet for 1 week each and then euthanized and kidneys extracted...Next, mpkCCD cells were incubated with PSC833 (PSC, 5 μM), an ABCA1 inhibitor, which increased abundance of pERK, (1.7±0.3; n=4; p<0.05) vs. untreated cells (1.0±0.2; n=4)... ABCA1 deficiency induces TLR4 and pERK abundance in renal CD while in mpkCCD cells exposed to FSS or ABCA1 inhibition sensitizes them to TLR4 dependent AIsc. We speculate repression of chol efflux enhances TLR4 dependent activation of pERK and AIsc."

IO biomarker • Cardiovascular • ABCA1 • TLR4