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BACKGROUND AND OBJECTIVE Although the anticancer potentials of water insoluble drugs are improved by nanoformulation, other intervening factors may contribute in the drug efficacy. This work was designated to explore the effect of paclitaxel-loaded poly lactic-co-glycolic acid (PLGA) nanoparticles on the viability of cancer cells, the expression of Taxol resistance gene I (TXR1) and paclitaxel metabolizing genes. METHODS Paclitaxel loaded PLGA nanoparticles (PTX-NPs) were prepared, physically characterized and used in treatment of breast adenocarcinoma cells (MCF-7) and hepatoma cells (HepG2). Cells viability and apoptosis were investigated. In parallel, RNA was isolated, reverse transcribed and used to monitor the expression levels of TXR1, CYP 3A4 and CYP2C8 genes. RESULTS PTX-NPs were characterized by transmission electron microscopy as a nano size sphere-like shape. FTIR analysis revealed good coupling between PTX and PLGA. The encapsulation efficiency was 99% and the drug release demonstrated a progressive releasing phase followed by slower and sustained releasing phase. Although HepG2 cells demonstrated more resistance to PTX than MCF-7 cells, both cell types were more responsive to PTX-NPS compared to PTX. The IC50 values decreased from 19.3 to 6.7 in breast cancer cells and from 42.5 to 13.1 g/ml in hepatoma cells. The apoptosis was the key mechanism in both cells, where at least 44% of cells underwent apoptosis. The expression of TXR1 decreased when either cells were treated to PTX-NPs, respectively, meanwhile the expression of CYP3A4 and CYP2C8 were increased. CONCLUSION Taken together, this in vitro study reports the associations between the enhanced responsiveness of MCF-7 and HepG2 cells to PLGA-loaded paclitaxel nanoparticles and the accompanying decrease in cells resistance to the PTX and its enhanced metabolism.