Potentiation of scutellarin on human tongue carcinoma xenograft by low-intensity ultrasound

Scutellarin 7-O-β-d-glucuronide (scutellarin) has shown great potential as a chemotherapeutic agent for cancer treatment, but only at high dosage. Here we investigate the possibility of using low intensity ultrasound to reduce the scutellarin dosage. Ultrasound intensities of 1.0 W/cm(2) and 0.05 W/cm(2) were used for in vivo and in vitro experiments, respectively, and a very low dosage of scutellarin (15 nM) was used. Tumor-bearing Balb/c mice and SAS human-tongue squamous carcinoma cell suspensions were used for the in vivo and in vitro experiments, respectively. Each kind of subjects was divided into control, ultrasound-alone, scutellarin-alone, and combined ultrasound-scutellarin treatment groups. Only the combined treatment showed strong anticancer effects. In the in vivo case, the combined treatment significantly delayed tumor growth, initiated cellular chromatin changes (including a decrease in the number of cytoplasmic organelles and fragmentation of condensed nuclear chromatin), inhibited tumor angiogenesis and lymphangiogenesis, stopped cancer-cell proliferation, decreased MMP-2 and MMP-9 expression levels and caused cancer-cell apoptosis. In the in vitro case, the combined treatment produced cancer cell-shape irregularity in a manner seriously fractured microvilli, inhibited cancer-cell migratory and invasion activities, and induced cancer-cell apoptosis. Because the combined treatment did not increase intracellular ROS production, scutellarin is not a sonosensitizer so that the anticancer effect is not through sonodynamic therapy. Low-intensity ultrasound is merely increasing the permeability of scutellarin into cancer cells. Based on our results, one may perform localized chemotherapy using much reduced dosage of the drug with the help of low intensity ultrasound, which will greatly minimize side effects.