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

Alessandro Colapietro; Alessandra Rossetti; Andrea Mancini; Stefano Martellucci; Giuseppe Ocone; Fanny Pulcini; Leda Biordi; Loredana Cristiano; Vincenzo Mattei; Simona Delle Monache; Francesco Marampon; Giovanni Luca Gravina; Claudio Festuccia

doi:10.3390/ph14111082

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 (Basel). 2021 Oct 26;14(11):1082. doi: 10.3390/ph14111082.

Authors

Affiliations

¹ Laboratory of Radiobiology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
² Biomedicine and Advanced Technologies Rieti Center, Sabina Universitas, 02100 Rieti, Italy.
³ Laboratory of Vascular Biology and Stem Cells, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
⁴ Laboratory of Medical Oncology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
⁵ Department of Clinical Medicine, Public Health, Division of Human Anatomy, University of L'Aquila, 67100 L'Aquila, Italy.
⁶ Department of Radiological, Oncological and Pathological Sciences, La Sapienza University of Rome, 00185 Rome, Italy.
⁷ Department of Biotechnological and Applied Clinical Sciences, Division of Radiotherapy, University of L'Aquila, 67100 L'Aquila, Italy.

Abstract

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.

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