Human serum albumin-bound paclitaxel nanoparticle inhibits cervical carcinoma cell proliferation and oxidative damage through CYP3A4 and CYP2C8

Abstract

BackgroundCervical cancer (CC) is currently the most common malignant tumour in the female reproductive tract, and paclitaxel (PTX) is a commonly used chemotherapeutic agent, but tumour cell resistance will seriously affect the therapeutic efficacy of PTX. Nanoparticle human serum albumin-bound paclitaxel (Nano-HSA-PTX) is a novel drug delivery modality that may have superior effects to PTX alone. ObjectiveTo clarify the effect of Nano-HSA-PTX on cervical carcinoma (CC) cells and the underlying mechanisms. MethodsAfter the preparation of Nano-HSA-PTX, its morphology was observed by electron transmission microscope (TEM), and its entrapment efficiency (EE%) and drug loading rate (DL%) were detected. Nano-HSA-PTX was compared with conventional PTX for drug metabolism. Additionally, CC HeLa and SiHa cells were purchased and divided into three groups to treat with Nano-HSA-PTX, PTX and normal saline, respectively. MTT, cell cloning, Transwell and cell scratch assays were carried out to determine cell proliferation, invasion and migration, flow cytometry and Western blotting were performed to detect apoptosis rate and apoptosis-related protein expression, and PCR was conducted to quantify oxidative damage indicators. Further, CYP3A4 and CYP2C8 expression patterns in CC cells (HeLa and SiHa) and human normal cervical epithelia (End1/E6E7) and the changes of their levels under the intervention of Nano-HSA-PTX were measured. Subsequently, C57BL/6mice were purchased for subcutaneous tumorigenesis experiment to observe the impact of Nano-HSA-PTX on tumor growth. ResultsUnder TEM, Nano-HSA-PTX was complete and arranged compactly, with a stable structure and markedly higher EE% and DL% than PTX (P < 0.05). Under Nano-HSA-PTX intervention, the proliferation, invasion, migration and oxidative damage of HeLa and SiHa were significantly decreased compared with the control and PTX groups, while the apoptosis was increased (P < 0.05). Besides, elevated CYP3A4 and CYP2C8 levels were observed in CC cells, which were inhibited by Nano-HSA-PTX and PTX (P < 0.05). Finally, tumorigenesis experiments in nude mice revealed that Nano-HSA-PTX could inhibit tumor growth. ConclusionCompared with PTX, Nano-HSA-PTX has a superior effect of inhibiting CC activity. And this mechanism of action was carried out by inhibiting the expression of CYP3A4 and CYP2C8.