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Direct inhibition of Retinoblastoma phosphorylation by Nimbolide causes cell cycle arrest and suppresses Glioblastoma growth

Karkare, Swagata
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1380613326

Abstract Details

2013, MS, University of Cincinnati, Pharmacy: Pharmaceutical Sciences.
Glioblastoma multiforme (GBM) is the most common and, simultaneously, most aggressive form of primary brain tumor occurring in human adults. Despite clinical application of various chemotherapy regimens, radiation, and surgical approaches, the median survival of patients after GBM diagnosis does not exceed 15 months. This underscores the urgent need for development of new synthetic or naturally-derived therapeutic agents, which not only extend median survival beyond 15 months but also offer the potential for cure. Recent advances in delineating the contributions of distinct signaling pathways and genetic alterations in tumorigenesis offer new therapeutic targets for pharmacological interventions in GBM patients. For centuries, medicinal plants were used as essential sources for the discovery of new anticancer agents. However, to rise to the level of clinically valuable adjuvants in cancer patients, it is imperative to understand the mechanisms of action associated with plant extracts or individual components purified from medicinal plants. Using contemporary molecular biology techniques, the results from this study demonstrate that pharmacologically active ingredients present in the ethanol-soluble fraction of Azadirachta Indica (Neem) leaves (Azt), including nimbolide, induce significant cytotoxicity against GBM cells in vitro and in vivo. Azt caused cell cycle arrest, most prominently at the G1-S border in GBM cells expressing the EGFRvIII oncogene, which is present in about 20-25% of glioblastomas. Azt directly inhibited kinase activity of the cyclin-dependent kinases CDK4/CDK6 leading to hypophosphorylation of the retinoblastoma (RB) protein and cell cycle arrest at G1-S. Independent of RB hypophosphorylation, Azt also significantly reduced proliferative and survival advantage of GBM cells by downregulating Bcl2 and blocking growth factor-induced phosphorylation of Akt, Erk1/2 and STAT3, respectively. In contrast, mTOR and other cell cycle regulators were not affected by Azt. Following intratumoral injection of Azt using a subcutaneous mouse GBM xenograft model, initiation and glioblastoma growth were significantly reduced as compared to ethanol treated controls. Taken together, our findings demonstrate that Azt and nimbolide effectively suppress growth of glioma cells in vitro and in vivo through interference with vital cell cycle regulators such as RB. These findings suggest that nimbolide may offer substantial clinical benefit for GBM patients and, thereby, holds incredible promises for future clinical studies.
Giovanni Pauletti, Ph.D. (Committee Chair)
Biplab Dasgupta, Ph.D. (Committee Member)
Gerald Kasting, Ph.D. (Committee Member)
77 p.
Oncology
Ethanolic Neem leaf extract; Azadirachta indica; Neem; Glioblastoma Multiforme; Anticancer; Natural products

Recommended Citations

Citations

  • Karkare, S. (2013). Direct inhibition of Retinoblastoma phosphorylation by Nimbolide causes cell cycle arrest and suppresses Glioblastoma growth [Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1380613326

    APA Style (7th edition)

  • Karkare, Swagata. Direct inhibition of Retinoblastoma phosphorylation by Nimbolide causes cell cycle arrest and suppresses Glioblastoma growth. 2013. University of Cincinnati, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1380613326.

    MLA Style (8th edition)

  • Karkare, Swagata. "Direct inhibition of Retinoblastoma phosphorylation by Nimbolide causes cell cycle arrest and suppresses Glioblastoma growth." Master's thesis, University of Cincinnati, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1380613326

    Chicago Manual of Style (17th edition)

ucin1380613326
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This open access ETD is published by University of Cincinnati and OhioLINK.