Determine the Antimetastasis Effect of Artesunate in Lung Cancer-Driven Brain Metastasis Model.

Abstract

Brain metastasis (BM), most vital and common metastasis phenotype occurs during tumorigenesis, the incidence of which varied remarkedly in various cancers. Overwhelming evidence suggested blood-brain barrier (BBB) can attenuate the anti-BM efficacy of chemotherapies via hindering their penetration. This study aimed to investigate the preferential cancer type that is more prone to BM, and bioactive compound that suppress BM through penetrating BBB. By intracardiac injection of lung cancer cells, breast cancer cells and melanoma cells, BM models were established. By two cycles of primary-isolation and incubation of H446-luc cells to improve the incidence of BM. Artemisinin (ART) and its derivatives were evaluated to suppress BM in vitro and in vivo. Compared to lung cancer-driven BM (66.67%), the incidence of BM in breast cancer (16.67%-33.33%) and melanoma (33.33%) were extremely low. The incidence of BM in lung cancer increased from 66.67 (1st generation) to 80% (2nd generation). Compared to other ingredients, artesunate (ARTS) exerted a more significant inhibitory effect on cell proliferation, especially in lung cancer cells. Simultaneously, ARTS suppressed lung cancer migration via decreasing N-cadherin and Snail, and enhancing E-cadherin. Most importantly, we found that ARTS could strikingly suppress tumor growth in brain with high concentration, implying that ARTS might penetrate BBB and accumulate in brain tissue to hinder lung cancer-driven BM. Our findings not only suggest lung cancer exhibited tumor specificity in cancer-driven BM model, but also provide ARTS as a promising candidate for clinical treatment of lung cancer-relayed BM.