Abstract
Simple SummarySince 2005, temozolomide (TMZ) has been used as a standard first-line treatment for glioblastoma (GBM, grade IV glioma), and despite many studies and efforts no better alternatives have emerged. Tumor recurrences and TMZ resistance are common and the prognosis is very poor with a median overall survival of 14–16 months. The development of new pharmacological strategies is even more difficult due to the presence of glioma stem cells (GSCs). In this multidisciplinary study, we tested the imidazobenzoxazin-5-thione MV1035, alone and in combination with TMZ, in U87-MG and patient-derived (PD) GSCs in order to demonstrate a putative synergic effect. MV1035 was tested following its in silico predicted ability to act as an inhibitor against ALKBH2 and ALKBH5, both involved in maintaining the tumorigenicity of glioblastoma.Glioblastoma (GBM, grade IV glioma) represents the most aggressive brain tumor and patients with GBM have a poor prognosis. Until now surgical resection followed by radiotherapy and temozolomide (TMZ) treatment represents the standard strategy for GBM. We showed that the imidazobenzoxazin-5-thione MV1035 is able to significantly reduce GBM U87-MG cells migration and invasiveness through inhibition of the RNA demethylase ALKBH5. In this work, we focus on the DNA repair protein ALKBH2, a further MV1035 target resulting from SPILLO-PBSS proteome-wide scale in silico analysis. Our data demonstrate that MV1035 inhibits the activity of ALKBH2, known to be involved in GBM TMZ resistance. MV1035 was used on both U87-MG and two patient-derived (PD) glioma stem cells (GSCs): in combination with TMZ, it has a significant synergistic effect in reducing cell viability and sphere formation. Moreover, MV1035 induces a reduction in MGMT expression in PD-GSCs cell lines most likely through a mechanism that acts on MGMT promoter methylation. Taken together our data show that MV1035 could act as an inhibitor potentially helpful to overcome TMZ resistance and able to reduce GBM migration and invasiveness.
Highlights
Glioblastoma multiforme (GBM) is the most aggressive and malignant primary brain tumor, classified as WHO (World Health Organization) grade IV gliomas [1]
Since targeting multiple pathways involved in cancer development with a single compound represents a well-investigated approach to develop new cancer treatments [18], we investigated MV1035 ability to inhibit both ALKBH5 and ALKBH2 aiming to find a new drug able to hamper GBM progression and/or support TMZ therapy; combination therapy, especially for the most difficult to treat cancers, remains a keystone in therapy
With the aim of identifying MV1035 target proteins able to account for MV1035induced reduction of U87-MG glioblastoma cells migration and invasiveness, we performed an analysis of the whole protein database using the SPILLO-PBSS software
Summary
Glioblastoma multiforme (GBM) is the most aggressive and malignant primary brain tumor, classified as WHO (World Health Organization) grade IV gliomas [1]. GBM accounts for 69% of all gliomas and for 12–15% of all primary brain tumors [2]. There is no standardized second-line treatment after tumor recurrence [5]. Multiple factors contribute to the treatment-refractory nature of glioblastoma including infiltration of normal brain, limited drug delivery into regions of tumor with an intact blood–brain barrier (BBB), inter- and intra-tumoral molecular heterogeneity, and inherent chemo- and radio-resistance [6]. The marked intratumoral heterogeneity is due to the presence of different cell populations with distinct genetic mutations, differentiation status, and responses to external stimuli. These include tumor populations characterized by greater tumorigenic potential called glioma stem cells (GSCs)
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