Studies On The Structures And The Anticancer Mechanism Of Active Natural Products From Three Plants

Tumor is a common and severe health problem worldwide and leads to the rising high mortality over the past fifty years.Radiotherapy and chemotherapy cause DNA damage and cell death,achieving the purpose of the treatment of malignant tumor,and are widely used in cancer therapy.However,the resistance encountered during the course of cancer treatment is an important problem.Thus,exploring new treatments to enhance the sensitivity of cancer cells is essential.In order to seek new anti-cancer molecules from natural products through inhibiting the process of DNA damage repair,the structures,bioactive of cancer cell killing as well as the mechanisms of secondary metabolites from three plants were investigated.1)44 compounds were obtained from three plants?Calotropis gigantea,Decaspermum gracilentum,Salvia miltiorrhizae?,including 14 cardenolides,8diterpenoids,5 lignands,4 phloroglucols,1 triterpenoids and other types of compounds.5 new compounds were identified among these compounds.The cytotoxicity and Cdc25A/B enzyme inhibition of these compounds were tested.Most of cardenolides and tanshinones showed better cytotoxicity.?H2AX foci assay and Cdc25A/B enzyme in vivo assay indicated that cardenolide may be used as a radiosensitizer and tanshinones may be good inhibitors of Cdc25A/B.2)The compound from Calotropis gigantea,named CGN?coroglaucigenin?,displayed much lower cytotoxicity to normal lung epithelial cells?BEAS-2B?than cancer cells?A549?.Especially,the treatment with CGN?1?M?combined with X-ray irradiation induced higher radiosensitivity in human lung cancer cells but not in BEAS-2B.The expression levels of nuclear transcription factor Nrf2 and Nrf2-driven antioxidant molecule NQO-1 reduced in A549 cells after combined treatment compared to the radiation only.However,1?M of CGN had no toxicity and the levels of antioxidant molecules expression were higher in BEAS-2B cells when given the similar treatment as A549 cells.3)Cdc25 phosphatases function as important regulators of the cell cycle during normal eukaryotic cell division and the overexpression of Cdc25s are frequently observed in cancer and relate to cancer migration,high-grade tumors and poor prognosis.Thus,it is available to select the inhibitors of Cdc25 as the candidates of the anti-cancer drug.Our results showed that tanshinone IIA?1?and cryptotanshinone?2?isolated from the root of Salviae Miltiorrhizae efficiently arrested the cell cycle of cancer cells in the G₂/M phase through the inhibition assay of Cdc25A/B enzymes activities.The value of IC₅₀ of both 1 and 2's inhibitions on Cdc25A/B were at the micromolar level.Additionally,compounds 1 and 2 might act by occupying the active sites,which may provide a clue to guide further optimization of Cdc25 inhibitor from nature.Our results suggest that CGN is a very promising potential sensitizer for cancer radiotherapy,which not only inhibits the proliferation of cancer cells but also enhances the radiosensitivity of cancer cells through suppressing the expression of antioxidant molecules while there is no influence for normal cells.In addition,tanshinone may use as the anti-tumor drug via inhibiting the activity of Cdc25.