Study On Synergic Anticancer Effect Of Levistolide A And Vinorelbine On Human Non-small Cell Lung Carcinoma

Lung cancer is a disease with the most incidences and the leading cause of cancer-related deaths in the world. Treatment of these patients is based on surgery, but at diagnosis approximately 80 % of patients are in the stage IIIA-IV and inoperable. Chemotherapy is one of the most efficient ways to treat these patients. But lung cancer, especially non-small cell lung cancer, is resistant to anti-cancer drugs. It is very difficult to treat it efficiently in a normal way. Chinese medical clinic trial showed that compounds from Chinese Traditional blood-dissipated Medicine treat patients together with chemotherapy drug can overcome the drug-resistant of cancer cells, and achieve great success.In this study, an active compound was extract from Chinese Traditional Medicine, which was known as Levistolide A. The research was focus on the anti-cancer effect of Levistolide A alone and with NVB in vitro and in vivo. MTT assay and flow cytometric assay were used to study the anti-cancer effect and its mechanism. In vitro, the IC₅₀S of LA of H1299 and SPCA-1 cell were 21.38 μg/mL and 20.10 μg/mL. LA treatment for 48 hours dose-dependently induced G₀/G₁ and S phase arrest in H1299 cells. When treatment with high doses of LA (20 and 40 μg/mL) for 48 h, the percentage of sub-G1 phase increased from 6.40 % to 14.86 %, and G₀/G₁ and S phase cells increased. 40 μg/mL of LA treatment for 48 h caused significant loss of mitochondrial membrane potential, which suggested that LA-induced apoptosis was via mitochondrial pathway.Relative to single agents, combination treatment of LA and NVB enhanced NVB-induced apoptosis in both H1299 and SPCA-1 cell lines. In H1299 cell line, the IC₅₀ of NVB shafted from 315 ng/mL to 1 ng/mL. In SPCA-1 cells, the IC₅₀ of NVB alone-treated group was 4.4-folds higher than combination group. Combination of LA and NVB treatment for 48 h dose-dependently induced S and G₂/M arrest in H1299 cells and SPCA-1 cells respectively. After combination treatment for 48 h, the percentage of sub-G1 phase increased from 6.40 % and 4.99 % to 58.49 % and 62.11 % in H1299 and SPCA-1 cells respectively. After treated with combination of LA and NVB, the percentage of mitochondrial membrane potential loss cells were increased by 48.12 % and 72.21 % in H1299 and SPCA-1 cells respectively.In vivo, under identical experimental conditions, combination of LA and NVB treatment showed significant decrease in tumor weight compared with control, LA or NVB alone-treated groups. LA treatment did not cause any weight loss of the animals, suggesting that LA does not induce any deleterious effect under the present experimental conditions. Combination of LA and NVB can be given safely to inhibit NSCLC tumor growth.The results suggested that LA can inhibit H1299 growth and induce apoptosis. Furthemore low dose of LA (10 μg/mL) can enhance the NVB-induced apoptosis via mitochondrial pathway. LA also showed its anticancer and enhance NVB-induced apoptosis activity and hypotoxicity.