Although tremendous resources have been invested in the development of new cancer therapeutic drugs, there is still no ‘cure’ for cancer. The discovery and development of new and more efficacious anticancer drugs are therefore imperative. In our continuing effort to discover novel anticancer agents from plant resources, we have evaluated the anticancer properties of several thousand plant extracts. This has led to the discovery of a class of novel cyclopeptides (mavacyocines A–C) that contain unique amino acid residues. Mavacyocine A (MVA) displayed highly potent activity against a panel of cancer cell lines with IC50 values in the range of 0.05–2.0 nM. This activity level renders MVA one of the most powerful cancer cell killers discovered in nature. Our study also revealed that these cyclopeptides might possess very different anticancer mechanism of action from those of natural products such as paclitaxel, maytansine and vinblastine. MVA was further evaluated in MCF-7 and HCT116 xenograft mouse model studies. The in vivo data showed that the plant cyclopeptide displayed more potent tumor inhibition activity at doses of 1.0 and 2.0 mg/kg than did paclitaxel at a dose of 5.0 mg/kg. Considering their anticancer potency and the potential novel anticancer mechanism, these cyclopeptides are worthy of further chemical and biological studies. The current project is designed to pursue an in-depth study of MVA and its analogs to elucidate their anticancer potency. To achieve this goal, the following objectives and tasks are proposed. 1) To synthesize structurally similar analogs of MVA to increase cancer therapeutic potential. Examples may include mavacyocines D1–D4 (MVD1–MVD4). MVD1 has a simplified chemical structure in comparison with the natural compound MVA and can be obtained by using a more concise synthetic approach, MVD2 and MVD3 each contain an amine group with the potential to increase water solubility, and MVD4 contains a thiol group with the potential to link with an antibody for development as an antibody-drug conjugate (ADC) drug candidate. 2) To elucidate the anticancer effects and mechanism of action of the mavacyocines through different approaches including characterization of the transforming phenotype, cDNA gene analysis and affinity binding assays. 3) To assess the anticancer efficacy of the newly synthesized mavacyocines through in vitro and in vivo studies. Upon completion of the proposed studies we expect to provide sufficient evidence to support further development of mavacyocines as anticancer candidates with strong therapeutic efficacy.
|Effective start/end date||1/01/17 → 30/06/20|
UN Sustainable Development Goals
In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):
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