Colapietro Alessandro, Yang Peiying, Rossetti Alessandra, Mancini Andrea, Vitale Flora, Martellucci Stefano, Conway Tara L, Chakraborty Sharmistha, Marampon Francesco, Mattei Vincenzo, Gravina Giovanni Luca, Biordi Assunta Leda, Wei Daoyan, Newman Robert A, Festuccia Claudio
Laboratory of Radiobiology, Department of Biotechnological and Applied Clinical 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.
Front Pharmacol. 2020 Sep 11;11:552428. doi: 10.3389/fphar.2020.552428. eCollection 2020.
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 C0 extract of 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 and 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 tumor models. Both 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.
多形性胶质母细胞瘤（GBM）是最常见的原发性胶质肿瘤，尽管目前进行了广泛的治疗努力，但患者生存率仍然很低。新出现的证据表明，需要更有效的治疗方法来克服肿瘤异质性、耐药性和复杂的肿瘤支持微环境。PBI-05204是一种特殊配方的植物药，由一种改良的超临界CO提取物组成，该提取物在美国已针对多种晚期癌症患者进行了I期和II期临床试验。本研究旨在使用和癌症模型研究这种植物药对胶质母细胞瘤的抗肿瘤疗效，并探索其对胶质母细胞瘤干细胞的疗效。所有三种人GBM细胞系U87MG、U251和T98G均被PBI-05204以浓度依赖性方式抑制，其特征是诱导细胞凋亡，这通过膜联蛋白V染色增加和半胱天冬酶活性得到证明。在所有处理的人GBM细胞系中，PBI-05240抑制了与Akt和mTOR途径相关的蛋白质表达。PBI-05204显著抑制U87球体形成以及重要干细胞标志物如SOX2、CD44和CXCR4的表达。口服PBI-05204导致对U87MG、U251和T98G异种移植瘤生长的剂量依赖性抑制。此外，携带U87-Luc细胞作为原位模型的PBI-05204处理小鼠表现出肿瘤增殖的明显延迟和总生存期的显著延长。异种移植瘤切片的免疫组织化学染色显示Ki67和CD31阳性染色细胞的表达呈剂量依赖性下降，但TUNEL染色增加。PBI-05204代表了一种治疗胶质母细胞瘤的新型治疗性植物药方法，这在肿瘤模型中得到了显著反应的证明。肿瘤组织的细胞培养和免疫组织化学研究均表明药物诱导肿瘤细胞凋亡并抑制PI3k/mTOR途径以及癌症干性。鉴于PBI-05204已经在癌症患者的I期和II期临床试验中进行了研究，在这种难以治疗的脑癌的未来临床试验中应探索其与标准护理化疗和放疗联合使用时的疗效。
