Abstract
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/cm2 and 0.05 W/cm2 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.
Highlights
Oral squamous cell carcinoma (OSCC) is a common cancer of the head and neck region, characterized by an aggressive growth pattern, high degree of local invasiveness and cervical lymph node spread [1,2]
Lowlevel ultrasound-alone treatment failed to inhibit cell growth, but promoted cell proliferation (Fig. 2c). These results indicate that low-intensity ultrasound can significantly enhance scutellarin-induced cell damage and cell-growth inhibition, whereas low-level ultrasound alone increases total cell proliferation after 48 h
The results revealed that both the S and the Us groups experienced increased reactive oxygen species (ROS) generation compared with the C group (Fig. 5, p,0.01); and there is a moderate increase of ROS in the case of combined ultrasound+scutellarin therapy compared with scutellarin or low level ultrasound alone treatment groups (Fig. 5, p,0.05)
Summary
Oral squamous cell carcinoma (OSCC) is a common cancer of the head and neck region, characterized by an aggressive growth pattern, high degree of local invasiveness and cervical lymph node spread [1,2]. Despite recent advances in diagnostic methods and treatment strategies, the overall survival rate of patients with OSCC has not significantly improved. The poor prognosis of patients with OSCC, whose 5-year mortality rate is over 50% [1], is due to the disease’s tendency of strong local invasion and distant metastasis [3]. Induction chemotherapy generally provides local treatment or palliative therapy for patients with recurrent and/or metastatic disease [6]. These forms of treatment usually yield many side effects. Surgical treatment may require organ removal in the oral cavity, resulting in oral dysfunction, such as difficulty in eating, swallowing, and speaking
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