Multiple Antitumor Molecular Mechanisms Are Activated by a Fully Synthetic and Stabilized Pharmaceutical Product Delivering the Active Compound Sulforaphane (SFX-01) in Preclinical Model of Human Glioblastoma

Pharmaceuticals

Stefano Martellucci¹  Vincenzo Mattei¹  Loredana Cristiano²  Francesco Marampon³  Leda Biordi⁴  Giuseppe Ocone⁵  Alessandro Colapietro⁵  Alessandra Rossetti⁵  Claudio Festuccia⁵  Giovanni Luca Gravina⁵  Andrea Mancini⁵  Fanny Pulcini⁶  Simona Delle Monache⁶ 

[1] Biomedicine and Advanced Technologies Rieti Center, Sabina Universitas, 02100 Rieti, Italy;Department of Clinical Medicine, Public Health, Division of Human Anatomy, University of L’Aquila, 67100 L’Aquila, Italy;Department of Radiological, Oncological and Pathological Sciences, La Sapienza University of Rome, 00185 Rome, Italy;Laboratory of Medical Oncology, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy;Laboratory of Radiobiology, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy;Laboratory of Vascular Biology and Stem Cells, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy;

关键词: GBM;    sulforaphane;    SFX-01;    hypoxia;    epithelial-to-mesenchymal trans-differentiation (EMT);    stemness and tumor recurrence;   

DOI  :  10.3390/ph14111082

来源: DOAJ

【 摘 要 】

Frequent relapses and therapeutic resistance make the management of glioblastoma (GBM, grade IV glioma), extremely difficult. Therefore, it is necessary to develop new pharmacological compounds to be used as a single treatment or in combination with current therapies in order to improve their effectiveness and reduce cytotoxicity for non-tumor cells. SFX-01 is a fully synthetic and stabilized pharmaceutical product containing the α-cyclodextrin that delivers the active compound 1-isothiocyanato-4-methyl-sulfinylbutane (SFN) and maintains biological activities of SFN. In this study, we verified whether SFX-01 was active in GBM preclinical models. Our data demonstrate that SFX-01 reduced cell proliferation and increased cell death in GBM cell lines and patient-derived glioma initiating cells (GICs) with a stem cell phenotype. The antiproliferative effects of SFX-01 were associated with a reduction in the stemness of GICs and reversion of neural-to-mesenchymal trans-differentiation (PMT) closely related to epithelial-to-mesenchymal trans-differentiation (EMT) of epithelial tumors. Commonly, PMT reversion decreases the invasive capacity of tumor cells and increases the sensitivity to pharmacological and instrumental therapies. SFX-01 induced caspase-dependent apoptosis, through both mitochondrion-mediated intrinsic and death-receptor-associated extrinsic pathways. Here, we demonstrate the involvement of reactive oxygen species (ROS) through mediating the reduction in the activity of essential molecular pathways, such as PI3K/Akt/mTOR, ERK, and STAT-3. SFX-01 also reduced the in vivo tumor growth of subcutaneous xenografts and increased the disease-free survival (DFS) and overall survival (OS), when tested in orthotopic intracranial GBM models. These effects were associated with reduced expression of HIF1α which, in turn, down-regulates neo-angiogenesis. So, SFX-01 may have potent anti-glioma effects, regulating important aspects of the biology of this neoplasia, such as hypoxia, stemness, and EMT reversion, which are commonly activated in this neoplasia and are responsible for therapeutic resistance and glioma recurrence. SFX-01 deserves to be considered as an emerging anticancer agent for the treatment of GBM. The possible radio- and chemo sensitization potential of SFX-01 should also be evaluated in further preclinical and clinical studies.

【 授权许可】

Unknown