Mechanism of Induction of P-gp Activity During MET Induced by DEX in Lung Cancer Cell Line.

Lung cancer metastasis often leads to a poor prognosis for patients. Mesenchymal-epithelial transition (MET) is one key process associated with metastasis. MET has also been linked to multidrug drug resistance (MDR). MDR arises from the overactivity of drug efflux transporters such as P-glycoprotein (P-gp) which operate at the cell plasma membrane, under the regulatory control of the scaffold proteins ezrin (Ezr), radixin (Rdx), and moesin (Msn), collectively known as ERM proteins. The current study was intended to clarify the functional changing of P-gp and the underlying mechanisms in the context of dexamethasone (DEX)-induced MET in lung cancer cells. We found that the mRNA and membrane protein expression of Ezr and P-gp was increased in response to DEX treatment. Moreover, the DEX-treated group exhibited an increase in Rho123 efflux, and it was reversed by treatment with the P-gp inhibitor verapamil or Ezr siRNA. The decrease in cell viability with paclitaxel (PTX) treatment was mitigated by pretreatment with DEX. The increased expression and activation of P-gp during the progression of lung cancer MET was regulated by Ezr. The regulatory mechanism of P-gp expression and activity may differ depending on the cell status.

P-Glycoprotein-Mediated Interaction Is a Risk Factor for QT Prolongation in Concomitant Use of Antipsychotics and SSRIs as P-Glycoprotein-Mediated Inhibitors: Analysis of the Japanese Adverse Drug Event Report Database.

The inhibition of human ether-a-go-go-related gene (hERG) channels is a known cause of QT prolongation triggered by antipsychotic drugs. Our previous studies suggest that P-glycoprotein (P-gp)-mediated drug interactions may lead to increased gastrointestinal absorption of pimozide and its accumulation in cardiomyocytes, thereby enhancing the inhibitory effect of hERG channels. There is a paucity of epidemiological studies examining the risk of QT prolongation by antipsychotic drugs in terms of P-gp-mediated interactions with concomitant drugs. Therefore, using the Japanese Adverse Event Reporting Database, we investigated whether the risk of QT prolongation triggered by antipsychotic drugs associated with hERG inhibition is affected by the concomitant use of selective serotonin reuptake inhibitors (SSRIs) associated with P-gp inhibition. The results showed that the frequency of QT prolongation increased when the antipsychotic drugs quetiapine and sulpiride, which are P-gp substrates, were combined with SSRIs with P-gp inhibition. In contrast, no association with QT prolongation was observed in patients on non-P-gp-substrate antipsychotics, irrespective of the P-gp inhibitory effect of the concomitant SSRI. These results suggest that P-gp-mediated interactions are a risk factor for antipsychotic-induced QT prolongation. There is a need for further investigation into the risks of specific drug combinations.

Impact of P-Glycoprotein-Mediated Drug-Endogenous Substrate Interactions on Androgen and Blood-Brain Barrier Permeability.

This report focuses on pharmacokinetic drug-endogenous substrate interactions (DEIs). We hypothesized that P-glycoprotein (P-gp)-mediated DEI might affect androgen kinetics, especially its blood-brain barrier (BBB) permeability. The intracellular accumulation of the endogenous substrates of P-gp, testosterone (TES) and androstenedione (ADO) was increased by several tested drugs in uptake studies using P-gp overexpressing cells, indicating that these drugs inhibit P-gp-mediated efflux of TES of ADO from the cells. In a transport study using rat BBB kit, we found that the BBB limited the penetration of TES and ADO into the central nervous system. In addition, tested drugs that cause DEI were found to increase BBB permeability of TES and ADO via P-gp inhibition. In short, this study provides new findings regarding the possibility that DEI may affect the kinetics of endogenous substrates of P-gp.

Therapeutic response and prognostic factors of 14 dogs undergoing transcatheter arterial embolization for hepatocellular masses: A retrospective study.

BACKGROUND: Information regarding the therapeutic effect and outcome of transcatheter arterial embolization (TAE) for hepatic masses is limited in veterinary medicine. HYPOTHESIS/OBJECTIVES: To analyze the therapeutic response, outcome (overall survival), and their predictors in dogs that underwent TAE for primary hepatocellular masses. We hypothesized that larger pre-TAE tumors would be associated with worse outcomes. ANIMALS: Fourteen client-owned dogs. METHODS: Retrospective study. Medical records between 1 September 2016 and 30 April 2022 were reviewed to identify dogs treated with TAE for hepatic masses diagnosed as hepatocellular origin by cytological or histopathological examination. Computed tomography images were compared before and after TAE. The univariate Cox proportional hazards test was performed to assess the associations between variables and survival. Univariate linear regression analysis was performed to assess the associations between variables and the tumor reduction percentage: ([post-TAE volume - pre-TAE volume]/pre-TAE volume) × 100. RESULTS: The median survival time was 419 days (95% confidence interval, 82-474). History of intra-abdominal hemorrhage (P = .03) and pre-TAE tumor volume/body weight (P = .009) were significantly associated with overall survival. The mean reduction percentage was -51% ± 40%. Pre-TAE tumor volume/body weight ratio (cm3 /kg; P = .02, correlation coefficient = 0.704) was significantly correlated with the volume reduction percentage. CONCLUSIONS: History of intra-abdominal hemorrhage and large pre-TAE tumor volume/body weight ratio could be predictive factors for adverse outcomes after TAE. Pre-TAE tumor volume/body weight ratio could be a predictive factor for therapeutic effect.

Microwave ablation for the control of bleeding from disintegrated mammary tumours in two dogs.

A 16-year-old intact female Miniature Dachshund (dog 1) and a 13-year-old intact female American Cocker Spaniel (dog 2) presented with a chief complaint of bleeding from a mammary gland tumour ulceration. Dog 1 was transferred to hospital from a local hospital in a haemorrhagic shock state with uncontrolled continuous bleeding. Thoracic radiographs revealed multiple nodular shadows suspected to be pulmonary metastasis. Dog 2 presented with intermittent bleeding from a mass lesion in the right fifth mammary gland. Due to high anaesthetic risk secondary to severe mitral valve insufficiency (ASA status III), the owner declined surgical excision of the tumour. Therefore, microwave ablation (MWA) under local anaesthesia was chosen in order to achieve adequate haemostasis. Both dogs received local anaesthesia around the bleeding mass lesion, and the disintegrated site was microwave-ablated; dog 1 underwent MWA after blood transfusion to improve the haemorrhagic shock. The ablation site was protected using a non-adhesive dressing. Scarring of the ulcerated site led to complete haemostasis in both cases. Dog 1 underwent tumorectomy on the 31st hospital day to prevent rebleeding; histopathology results were consistent with mammary adenocarcinoma with the ablation site covered by a capsule structure. To the authors' knowledge, this is the first case report describing the use of MWA to stop bleeding from mammary tumours in veterinary medicine. MWA is a feasible and potentially effective palliative treatment modality to stop bleeding from disintegrated mammary tumours in dogs under local anaesthesia.

Slug Mediates MRP2 Expression in Non-Small Cell Lung Cancer Cells.

Transcriptional factors, such as Snail, Slug, and Smuc, that cause epithelial-mesenchymal transition are thought to regulate the expression of Ezrin, Radixin, and Moesin (ERM proteins), which serve as anchors for efflux transporters on the plasma membrane surface. Our previous results using lung cancer clinical samples indicated a correlation between Slug and efflux transporter MRP2. In the current study, we aimed to evaluate the relationships between MRP2, ERM proteins, and Slug in lung cancer cells. HCC827 cells were transfected by Mock and Slug plasmid. Both mRNA expression levels and protein expression levels were measured. Then, the activity of MRP2 was evaluated using CDCF and SN-38 (MRP2 substrates). HCC827 cells transfected with the Slug plasmid showed significantly higher mRNA expression levels of MRP2 than the Mock-transfected cells. However, the mRNA expression levels of ERM proteins did not show a significant difference between Slug-transfected cells and Mock-transfected cells. Protein expression of MRP2 was increased in Slug-transfected cells. The uptake of both CDCF and SN-38 was significantly decreased after transfection with Slug. This change was abrogated by treatment with MK571, an MRP2 inhibitor. The viability of Slug-transfected cells, compared to Mock cells, significantly increased after incubation with SN-38. Thus, Slug may increase the mRNA and protein expression of MRP2 without regulation by ERM proteins in HCC827 cells, thereby enhancing MRP2 activity. Inhibition of Slug may reduce the efficacy of multidrug resistance in lung cancer.