Antioxidant And Anti-tumor Properties Of Four Kinds Of Natural Products And Their Derivatives

To find effective antioxidants from natural products to prevent or therapy diseases related to free radicals and to search safe and efficient lead compounds for cancer therapy. The antioxidant and anti-tumor properties of four kinds of natural products and their derivatives were investigated in this research.Different in vitro antioxidant models, such as scavenging superoxide anion and 1,1-diphenyl-2- picrylhydrazyl (DPPH), inhibiting rat liver or brain homogenates lipid peroxidation, chelating ferrous ion (Fe²⁺), as well as inhibiting the insult of the plasmid DNA and rat pheochromocytoma (PC12) cells induced by hydrogen peroxide (H₂O₂), were employed to evaluate the antioxidant activities of silybin derivatives (compounds 1.1-1.22), neolignan derivatives (compounds2.1-2.14), and diarylheptanoids isolated from Zingiber officinale (compounds 3.1-3.5).Moreover, we also evaluated the in vitro cytotoxicity of compounds 3.1-3.5 and 4.1 (isolated from Ligularia atroviolacea) against human tumor cells by MTT assay. The possible antitumor mechanism of compound 4.1 was investigated in human chronic myelogenous leukemia (K562) cell line. The morphological change of K562 cells treated by compound 4.1 was observed on inverted microscope. Cell morphology of compound 4.1-induced apoptosis was investigated by staining the cells with JC-1 and a combination of the fluorescent DNA-binding dyes acridine orange (AO) and ethidium bromide (EB). Western blot analysis was used to examine the expression changes of apoptosis-related proteins, including ERK1/2, JNK, Bcl-2 and Bax, as well as the cell-cycle-related proteins, such as CDK2 and CDK4. The flow cytometry analysis was used to investigate the apoptosis and the changes of cell-cycle distribution.The results of in vitro antioxidant assay are listed as follows. 1) Silybin derivatives possessed different antioxidant properties. The study of SARs indicated that the alkoxy moiety substituted on the ortho of phenolic hydroxyl group of E ring can increase the efficacy of compounds 1.1-1.8, and the electron density of the substitutents plays an important role on the antioxidative effects of compounds 1.9-1.22. 2) The data obtained from in vitro and cell models demonstrated that the neolignan derivatives 2.4 and 2.13 exhibited remarkable antioxidative and neuroprotective activities. 3) Compounds (3.1-3.5) showed significant antioxidant activities. However, the pro-oxidant activity of compounds 3.1 and 3.5 was also observed.The MTT test revealed that compound 3.3 exhibited certain cytotoxicities against human chronic myelogenous leukemia cells (K562) and its adriamycin-resistant cells (K562/ADR).The growth of different human cancer cell lines was inhibited by compound 4.1 in vitro assays and the drug resistance of K562/ADR was reversed after being treated with compound 4.1 in a dose-dependent manner. The study of its possible mechanisms exhibited that ERK1/2 and JNK pathway mediated the K562 cells apoptosis and G1 arrest induced by compound 4.1. This is the first time to report the antitumor activity and its possible mechanism of compound 4.1, and it might provide significant information for further exploring this compound as a novel antitumor agent.