The Botanical Drug PBI-05204, a Supercritical CO2 Extract of Nerium Oleander, Inhibits Growth of Human Glioblastoma, Reduces Akt/mTOR Activities, and Modulates GSC Cell-Renewal Properties

Frontiers in Pharmacology

Daoyan Wei¹  Francesco Marampon²  Sharmistha Chakraborty³  Peiying Yang³  Tara L. Conway³  Giovanni Luca Gravina⁴  Stefano Martellucci⁶  Flora Vitale⁷  Vincenzo Mattei⁷  Alessandro Colapietro⁸  Alessandra Rossetti⁸  Assunta Leda Biordi⁸  Claudio Festuccia⁸  Andrea Mancini⁸  Robert A. Newman⁹ 

[1] Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, United States;Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy;Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States;Division of Radiation Oncology, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy;Laboratory of Cellular Pathology, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy;Laboratory of Experimental Medicine and Environmental Pathology, University Hub “Sabina Universitas”, Rieti, Italy;Laboratory of Neurophysiology, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy;Laboratory of Radiobiology, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy;Phoenix Biotechnology, Inc., San Antonio, TX, United States;

关键词: glioblastoma;    glioblastoma stem cells;    PBI-05204;    PI3k/mTOR;    Nerium oleander;   

DOI  :  10.3389/fphar.2020.552428

来源: DOAJ

【 摘 要 】

Glioblastoma multiform (GBM) is the most common primary glial tumor resulting in very low patient survival despite current extensive therapeutic efforts. Emerging evidence suggests that more effective treatments are required to overcome tumor heterogeneity, drug resistance and a complex tumor-supporting microenvironment. PBI-05204 is a specifically formulated botanical drug consisting of a modified supercritical C02 extract of Nerium oleander that has undergone both phase I and phase II clinical trials in the United States for treatment of patients with a variety of advanced cancers. The present study was designed to investigate the antitumor efficacy of this botanical drug against glioblastoma using both in vitro and in vivo cancer models as well as exploring efficacy against glioblastoma stem cells. All three human GBM cell lines, U87MG, U251, and T98G, were inhibited by PBI-05204 in a concentration dependent manner that was characterized by induction of apoptosis as evidenced by increased ANNEXIN V staining and caspase activities. The expression of proteins associated with both Akt and mTOR pathway was suppressed by PBI-05240 in all treated human GBM cell lines. PBI-05204 significantly suppressed U87 spheroid formation and the expression of important stem cell markers such as SOX2, CD44, and CXCR4. Oral administration of PBI-05204 resulted in a dose-dependent inhibition of U87MG, U251, and T98G xenograft growth. Additionally, PBI-05204–treated mice carrying U87-Luc cells as an orthotropic model exhibited significantly delayed onset of tumor proliferation and significantly increased overall survival. Immunohistochemical staining of xenograft derived tumor sections revealed dose-dependent declines in expression of Ki67 and CD31 positive stained cells but increased TUNEL staining. PBI-05204 represents a novel therapeutic botanical drug approach for treatment of glioblastoma as demonstrated by significant responses with in vivo tumor models. Both in vitro cell culture and immunohistochemical studies of tumor tissue suggest drug induction of tumor cell apoptosis and inhibition of PI3k/mTOR pathways as well as cancer stemness. Given the fact that PBI-05204 has already been examined in phase I and II clinical trials for cancer patients, its efficacy when combined with standard of care chemotherapy and radiotherapy should be explored in future clinical trials of this difficult to treat brain cancer.

【 授权许可】

Unknown