Yeshavanth Kumar Banasavadi-Siddegowda1,2, Alessandra M Welker3,4,5, Min An3, Xiaozhi Yang6, Wei Zhou7, Guqin Shi8, Jaime Imitola9, Chenglong Li6,7,8, Sigmund Hsu1, Jiang Wang10, Mitch Phelps10, Jianying Zhang11, Christine E Beattie3, Robert Baiocchi12, Balveen Kaur1,2. 1. The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas. 2. Department of Neurological Surgery, College of Medicine, The Ohio State University, Columbus, Ohio. 3. Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, Ohio. 4. Department of Pathology, Center of Cancer Research, Massachusetts General Hospital, Boston, Massachusetts. 5. Harvard Stem Cell Institute, Boston, Massachusetts. 6. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida. 7. Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida. 8. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio. 9. Laboratory for Neural Stem Cells and Functional Neurogenetics, Division of Neuroimmunology and Multiple Sclerosis, Departments of Neurology and Neuroscience, College of Medicine, The Ohio State University, Columbus, Ohio. 10. Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio. 11. Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio. 12. College of Medicine, Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
Abstract
Background: In spite of standard multimodal therapy consisting of surgical resection followed by radiation and concurrent chemotherapy, prognosis for glioblastoma (GBM) patients remains poor. The identification of both differentiated and undifferentiated "stem cell like" populations in the tumor highlights the significance of finding novel targets that affect the heterogeneous tumor cell population. Protein arginine methyltransferase 5 (PRMT5) is one such candidate gene whose nuclear expression correlates with poor survival and has been reported to be required for survival of differentiated GBM cells and self-renewal of undifferentiated GBM cells. In the current study we screened the specificity and efficacy of 4 novel PRMT5 inhibitors in the treatment of GBM. Methods: Efficacies of these inhibitors were screened using an in vitro GBM neurosphere model and an in vivo intracranial zebrafish model of glioma. Standard molecular biology methods were employed to investigate changes in cell cycle, growth, and senescence. Results: In vitro and in vivo studies revealed that among the 4 PRMT5 inhibitors, treatment of GBM cells with compound 5 (CMP5) mirrored the effects of PRMT5 knockdown wherein it led to apoptosis of differentiated GBM cells and drove undifferentiated primary patient derived GBM cells into a nonreplicative senescent state. Conclusion: In vivo antitumor efficacy combined with the specificity of CMP5 underscores the importance of developing it for translation.
Background: In spite of standard multimodal therapy consisting of surgical resection followed by radiation and concurrent chemotherapy, prognosis for glioblastoma (GBM) patients remains poor. The identification of both differentiated and undifferentiated "stem cell like" populations in the tumor highlights the significance of finding novel targets that affect the heterogeneous tumor cell population. Protein arginine methyltransferase 5 (PRMT5) is one such candidate gene whose nuclear expression correlates with poor survival and has been reported to be required for survival of differentiated GBM cells and self-renewal of undifferentiated GBM cells. In the current study we screened the specificity and efficacy of 4 novel PRMT5 inhibitors in the treatment of GBM. Methods: Efficacies of these inhibitors were screened using an in vitro GBM neurosphere model and an in vivo intracranial zebrafish model of glioma. Standard molecular biology methods were employed to investigate changes in cell cycle, growth, and senescence. Results: In vitro and in vivo studies revealed that among the 4 PRMT5 inhibitors, treatment of GBM cells with compound 5 (CMP5) mirrored the effects of PRMT5 knockdown wherein it led to apoptosis of differentiated GBM cells and drove undifferentiated primary patient derived GBM cells into a nonreplicative senescent state. Conclusion: In vivo antitumor efficacy combined with the specificity of CMP5 underscores the importance of developing it for translation.
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