Ultrasound stimulated microbubble cavitation promoted the anticancer effect of Lenvatinib on anaplastic thyroid cancer.

BACKGROUND: Anaplastic thyroid cancer (ATC) is an extremely aggressive subtype of thyroid cancer associated with poor prognosis. Thus, the necessity to develop innovative treatment approaches is critical. Lenvatinib is the one of the drugs approved for ATC in clinic, however, its efficacy is limited. The present study investigated the combined effect of ultrasound stimulated microbubble cavitation (USMC) and Lenvatinib on tumor growth. METHODS: Undifferentiated thyroid carcinoma C643 cells were subcutaneously inoculated into mice to establish transplanted tumor model and mice were allocated into 4 groups (model group, Lenvatinib group, USMC group, and Lenvatinib + USMC group). Blood perfusion in tumors was estimated with contrast-enhanced ultrasound (CEUS) and the microvascular structures were observed by transmission electron microscopy. H&E and Masson staining was applied. Immunohistochemical staining for CD31, Ki67, Caspase 3 expression, ELISA for VEGFA, NO, and PGF2 levels, western blot for HIF-1α and Akt/PI3K proteins, and immunofluorescence for VEGFA and ICAM-1. RESULTS: USMC caused mild enlargement and congestion of tumor microvessels. Moreover, upon exposure to USMC, the area under the curve and peak intensity of CEUS (MI = 0.4) showed an increase, indicating that USMC has the potential to augment blood flow within tumors. The combination of USMC and Lenvatinib meaningfully suppressed tumor growth, induced apoptosis, inhibited Ki67 expression and extended the survival of mice bearing C643 tumor. USMC also improved the anti-angiogenesis effect of Lenvatinib, as demonstrated by decreased expression of collagen fiber, CD31, HIF-1α and VEGFA in tumors and inactivation of PI3K/Akt pathway. Increment in ICAM-1, PGF(2) and NO expression was also observed in the combination group. CONCLUSIONS: These results indicated that the combination of Lenvatinib and USMC could serve as a promising and innovative method for ATC therapy, surpassing the effectiveness of Lenvatinib monotherapy.