Enhancing the therapeutic efficacy of gefitinib on subcutaneously transplanted SKOV3 ovarian cancer tumors in nude mice via ultrasound‑stimulated microbubble cavitation.

Abstract

The present study aimed to explore the effect of ultrasound-stimulated microbubble cavitation (USMC) on drug concentration and therapeutic efficacy of oral gefitinib in treating subcutaneously transplanted SKOV3 ovarian cancer tumors in nude mice. The present study employed the VINNO70 ultrasonic diagnostic and treatment integrated machine for USMC therapy. Firstly, the mechanical index was set at 0.25, and the therapeutic efficacy of USMC treatment was assessed at intervals of 5, 10 and 20 min. Briefly, 72 nude mice were randomized into the following four groups (n=18/group): Control group, USMC5 min group, USMC10 min group and USMC20 min group, and the therapeutic response to USMC treatment was evaluated by comparing pre-and post-intervention effects. Additionally, the combined therapeutic efficacy of USMC and gefitinib was investigated by randomly dividing 96 tumor-bearing mice into the following four groups (n=24/group): Control group, USMC group, gefitinib group and USMC + gefitinib group. Contrast-enhanced ultrasound, hematoxylin and eosin staining, western blotting, immunofluorescence staining, TUNEL staining, ELISA and liquid chromatography-mass spectrometry were performed in the present study. The results showed that USMC combined with gefitinib had the best treatment effect; the tumor inhibition rate was higher than that of gefitinib alone and the overall survival time was prolonged. In addition, the drug concentration in the tumor tissue obtained from the USMC + gefitinib group was revealed to be ~1.4 times higher than that detected in the group treated with gefitinib alone. The experimental results also confirmed that the strongest tumor inhibition rate and longest overall survival time was observed in the USMC + gefitinib group, followed by the gefitinib group and USMC group. STAT3 is an important signaling transducer and transcription factor, which, when phosphorylated, can lead to abnormal cell proliferation and malignant transformation. In addition, the upregulation of phosphorylated (p)-STAT3 is consider a reason for the poor efficacy of gefitinib in treating ovarian cancer. The present study revealed that ultrasound microbubble therapy could overcome this side effect. In conclusion, USMC improved the effects of oral gefitinib on subcutaneously transplanted SKOV3 ovarian cancer tumors in nude mice and increased drug penetration. In addition, USMC overcame the gefitinib-induced side effect of upregulated STAT3 phosphorylation and reduced the expression levels of p-STAT3 in the tumor.