Proton Pump Inhibitors Modulate Transport Of Doxorubicin And Its Liposomal Form Into 2D And 3D Breast Cancer Cell Cultures

MiglÄ— PaškeviÄiÅ«tÄ—,1 Vilma PetrikaitÄ—1,2 1Laboratory of Drug Targets Histopathology, Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania; 2Institute of Physiology and Pharmacology, Faculty of Medicine, Lithuanian University of Health Sciences, Kaunas LT-44307, LithuaniaCorrespondence: Vilma PetrikaitÄ—Laboratory of Drug Targets Histopathology, Institute of Cardiology, Lithuanian University of Health Sciences, SukilÄ—lių Av. 13, Kaunas LT-50161, LithuaniaTel +370 686 29 383Email VilmaPetrikaite@lsmuni.ltPurpose: The purpose of our study was to evaluate the influence of two PPIs (omeprazole (OME) and lansoprazole (LANSO)) on weakly basic anticancer drug doxorubicin (DOX) and pegylated liposomal doxorubicin (PLD) delivery to monolayer-cultured 4T1 murine breast cancer cells and tumor spheroids.Methods: The effect of PPIs on cell viability was evaluated by MTT assay. 3D cell cultures (spheroids) were formed using 3D bioprinting method. DOX and PLD penetration into cancer cells and spheroids at pH 6.0 and 7.4 was assessed using fluorescence microscopy.Results: Both OME and LANSO did not reduce the viability of 4T1 cells at 100 μM and lower concentrations, and therefore, in further experiments, 100 μM of PPIs was used. At pH 7.4, both tested PPIs did not enhance DOX (5 μM) and PLD (concentration corresponding to 5 μM DOX) delivery into 2D cell cultures. However, in acidic conditions, both PPIs increased the amount of drug in cancer cells and their nucleus. At physiological pH they were not effective at improving DOX delivery into spheroids, but after 2 hrs of incubation, OME slightly increased PLD delivery into edge and middle zones. At pH 6.0, both tested PPIs significantly enhanced DOX and PLD transport into spheroids, but the positive effect on delivery was observed only within the first 4 hrs of incubation.Conclusion: Both OME and LANSO increased DOX and PLD penetration into monolayer-cultured cells at acidic conditions but did not show a positive effect on drug ...