Fisetin, a dietary flavonoid, binds to beta-tubulin, and disrupts microtubule dynamics in prostate cancer cells.

摘要

Despite advances in screening and treatment, prostate cancer (PCa) remains a leading cause of cancer related deaths among men in the United States. Androgen ablation therapy has been shown to be effective in regression of initial tumors; however, advanced PCa progresses to metastatic castration-resistant PCa (mCRPC), for which there is no cure. An effective mechanism-based approach is needed so that long-term improvements can be achieved in the management of PCa. As such, a wide range of novel therapies have been introduced clinically for the treatment of mCRPC, including the use of microtubule targeting agents. Microtubules are unique in that they fill the entire cytoplasm from just outside the nucleus all the way to the plasma membrane, providing ample surface for protein-protein interactions. In addition, they have an inherent polarity allowing for the directional flow of information within the cell. As a result, small molecules that target microtubules disrupt all of these interactions and signal cascades, in addition to affecting mitosis. Since 1971 when it was discovered that taxol has anti-cancer activity in several experimental systems, therapy with taxanes has evolved into one of best known class of chemotherapeutic drugs for PCa. However, the effectiveness of these drug.;has been impaired by severe side effects and subsequent development of drug resistance. We advocate that natural agents from dietary sources could offer a safe and effective alternative in combination with standard of care to the existing repertoire of microtubule-targeting agents. We have observed that fisetin, a dietary 3, 3', 4', 7-tetrahydroxyflavone present in many vegetables and fruits, is a microtubule stabilizing agent that significantly affects microtubule dynamics. We hypothesized that fisetin will enhance the efficacy of cabazitaxel, a second generation taxol used in advanced and metastatic human PCa. To test our hypothesis, we employed in-vitro human PCa cells assays, in silico docking technique, and in-vivo animal model approaches. We determined the effect of fisetin alone and in combination with cabazitaxel. The combination significantly reduced the effective dose of cabazitaxel. These results suggest that fisetin can be used in combination with cabazitaxel to inhibit tumor growth and metastasis of advanced human PCa.