title: Natural Product Drug Discovery Targeting Cancer
Creators: name: Zhang, Qian
Publisher: name: Griffith University
Year: 2017
Subjects: subject: Natural medicines
subject: Cancer

description: Chemotherapy is one of the most effective approaches for cancer treatment. However, to improve efficacy, the therapeutic targets should be identified and characterised. Moreover, new drugs need to be discovered and developed to target different cancer pathways. Current therapeutics can eliminate most of the cancer cells. However, recurrence and metastasis still remain a major failure of cancer therapy. Emerging evidence demonstrates that multidrug resistance (MDR) and the existence of cancer stem cells (CSCs) are two major contributors for the failure of chemotherapy. MDR is a phenomenon in which cancer cells become resistant to structurally and functionally unrelated anticancer agents. CSCs are a small population of cells within cancer cells with capacity for self-renewal, tumor metastasis and differentiation. CSCs are also believed to be associated with chemoresistance. Thus, MDR and CSCs are the greatest challenges for cancer chemotherapy. Significant effort has been made to search for agents that specifically target MDR cells and CSCs. Consequently, some agents derived from nature have been developed to overcome MDR and CSCs. However, the developed chemotherapeutics cannot be used for all the cancers and some of them display severe cytotoxicity. Hence, there is an urgency to investigate the mechanism of drug resistance and to characterise cancer stem cells to identify potential new therapeutic targets. Natural products lie in the heart of the drug discovery. The developed chemotherapeutic compounds mainly originates from the secondary metabolites of microbes, terrestrial plants and marine organisms. In this study, MDR cancer cells were derived from tissue cultured cancer cells by the treatment the cells with fluorouracil (5-FU) and cisplatin (CDDP). CSCs were developed by treatment in serum-free medium with different factors. Fractions and compounds from Nature Bank (Griffith Institute for Drug Discovery, Griffith University), Compounds Australia (Griffith Institute for Drug Discovery, Griffith University) and Traditional Chinese Medicine (TCM) were screening by high through-put screening (HTS). As a result, one potential anticancer flavonoid was isolated from the Australian plant Cryptocarya (QID025519) which was identified by NMR spectroscopic data, in combination with LC-MS. Extracts, fractions and isolated pure compounds from Bruguiera gymnorrhiza andSchisandraviridis were identified as potential agents for the treatment of tongue cancer and breast cancer. The DCM and MeOH extracts and HPLC fractions of B. gymnorrhiza showed antiproliferation activity against cancer cells in a concentration-dependent manner. Further purification of the active fractions led to the isolation of five flavonoids namely rutin, myricetin 3-rutinoside, methoxyflavone, 5-Methoxyluteolin, and 7,3',4',5'-tetrahydroxy-5- gramrione. All five compounds showed antiproliferation activity against CAL27 and MCF7 and MDR cells in a concentration-dependent manner. Methoxyflavone demonstrated the strongest anticancer potential against CAL27 cells, MCF7 cells, CAL27 MDR cells while 7,3',4',5'-tetrahydroxy-5- gramrione illustrated the highest inhibitory effect on MCF7 MDR cells. Both aqueous and ethanol extracts showed activities against MCF7 and CAL27 cancer cells. Bioassay-guided fractionation and purification of the extracts from S.viridis resulted in six active principles, including five dibenzocyclooctene lignans namely gomisin H (1), schisandrin (2), angeloylgomisin H (3), (+)-gomisin M2 (4) and rubschisandrin (5), and one terpenoid, schisanol (6). Compounds 1-3 showed moderate anticancer activities with an IC50 value ranging from 100-200 μg/mL against MCF7 and CAL27 cell lines. Dioxane containing lignans 4-5 and triterpenoid 6 were 10 times more active with IC50 values of14.5, 13.4, 10.6 μg/mL against MCF7, and 21.2, 17.9, 11.7 μg/mL against CAL27, respectively. In addition, two compounds from Compounds Australia exhibited a potential application prospects for tongue cancer and breast cancer therapy. One compound SN00802961 exhibited significant inhibition on MCF7 cells, but low inhibitory effects on fibroblast cells. Meanwhile, it exhibited moderate inhibition on CAL27 MDR cells, CAL27 cells and CSCs. Compound SN00802961 has potently targeted the MAPK/ERK1/2 signaling pathway to induce cytotoxicity in MCF7 cells. Another agent SN00771077 for breast cancer cells in vitro was investigated. The effects of compound SN00771077 on cell viability in vitro were evaluated by treatment of MCF-7 and T47D cells. An in vitro viability assay demonstrated that compound SN00771077 inhibited the cell growth in a dose-dependent manner. The antiproliferative activity of compound SN00771077 is related to its activity on monomeric actin and the subsequent inhibition of polymerization of G-actin monomers. Exposure to compound SN00771077 induced the inhibition of Raf/MEK/ERK pathway in T47D cells. All the results indicated that compound SN00771077 had a strong cytotoxic effects on cancer cells, and shows potential in the treatment of breast cancer by causing the depolymerizing actin cytoskeleton.