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Research - Preclinical development of a novel plant toxin, persin, as an anti-cancer agent |
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Breast cancer remains a major cause of cancer death, emphasising the need for the development of novel therapeutics with increased efficacy. A novel plant toxin called persin has unique specificity for the mammary gland, kills cultured breast cancer cells and makes them more responsive to the breast cancer drug, tamoxifen. To further develop this compound as a novel anti-cancer agent, it is critical to define its intracellular mode of action and determine its efficacy against breast tumours grown in mice. |
BACKGROUND:Phytochemicals have provided an abundant and effective source of novel therapeutics for the treatment of cancer. This research centres upon the further preclinical characterisation of a novel plant toxin, persin, that has unique, in vivo actions in the mammary gland and exhibits potent cytotoxic synergy with the breast cancer therapeutic, tamoxifen in both ER-positive and ER-negative breast cancer cells. The latter is dependent upon expression of the proapoptotic protein, Bim. Bim is a sensor of cytoskeletal integrity, and there is evidence that persin acts as a microtubule-stabilising agent. Due to the unique structure of the compound, persin could represent a novel class of microtubule-targeting agent with potential specificity for cancers of the breast, and potentially other organs. Critical steps in the evaluation of this compound are to elucidate its mechanism of action through definition and characterisation of its intracellular targets, and to evaluate its in vivo effectiveness. HYPOTHESIS/AIMS:We hypothesize that persin is a molecule with significant potential as an anti-cancer therapeutic, that mediates its cytotoxicity in human cancer cells by direct interaction with microtubules and through modulating ceramide metabolism.
The overall aim of this project is to further develop and evaluate the therapeutic potential of persin as an anti-cancer agent. This will be achieved by addressing two specific aims:
SIGNIFICANCE:Breast cancer remains a major cause of cancer death amongst women in developed countries. Despite advances in detection and treatment which have improved survival, intrinsic or acquired therapeutic resistance remains a major obstacle to an effective cure, emphasising the significant clinical need for the development of novel molecular therapeutics with increased selectivity and efficacy. Our previous studies have emphasised persin's significant potential as a novel therapeutic agent for the treatment of cancers of the breast, and potentially other organs. They have also provide the rationale for the further preclinical development of this compound or more effective synthetic analogues, with the potential to act as an innovative strategy to enhance and broaden therapeutic efficacy and counteract refractory disease.  Dr. Alison Butt Garvan Institute of Medical Research |
