RESUMO
BACKGROUND: Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer with poor prognosis. Artemisinin (AN), produced naturally in Artemisia annua L., has anti-cancer activity. Artemisinin delivered as dried leaf Artemisia (DLA) showed efficacy against malaria in rodents and humans. HYPOTHESIS/PURPOSE: DLA is posited as being at least as efficacious as artesunate (AS) in its ability to induce cytotoxicity in NSCLC cells and also inhibit tumor growth in a NSCLC xenograft murine model. STUDY DESIGN: Three NSCLC cell lines were used, a non-cancerous human fibroblast line, and xenograft murine models to compare efficacy of artemisinin delivered p.o. via DLA, DLA extracts (DLAe), and AS. METHODS: DLAe was compared to AS using NSCLC cell lines A549, H1299 and PC9 as well as non-cancerous human dermal fibroblasts (HDF) CCD-1108Sk line. Cell viability, cell migration and cell cycle were compared for AS and DLAe. Westerns measured activated caspases-3, -8 and -9 to determine involvement of intrinsic and/or extrinsic apoptotic pathways. Xenograft murine models of A549 and PC9 cells were used to measure tumor growth inhibition by AS or DLA, with tumor volume the primary endpoint. RESULTS: Both DLAe and AS suppressed A549, H1299 and PC9 cell viability with no inhibition of non-cancerous HDF CCD-1108Sk cells. Caspases-3, -8 and -9 were activated, suggesting cell death was stimulated through both intrinsic and/or extrinsic apoptotic pathways. Both drugs induced G2/M or mitotic arrest in PC9 and H1299 cells, and DLAe induced G1 arrest in A549 cells. AS and DLAe induced DNA damage as double stranded breaks evidenced by phosphorylation of histone H2AX. DLAe inhibited migration of PC9 and A549 cells. In A549 xenografted animals, p.o. AS and DLA inhibited relative tumor growth by 40% and 50%, respectively, compared to controls. AS was ineffective at inhibiting PC9-induced tumor growth, but DLA inhibited relative tumor growth by â¼50% compared to controls. CONCLUSION: This is the first study demonstrating efficacy of DLA and mechanistic differences of DLAe vs. AS, against NSCLC cells. Compared to AS, DLA possesses qualities of a novel therapeutic for patients with NSCLC.
