Repurposing drugs for glioblastoma: From bench to bedside

Basso, João; Miranda, Ana; Sousa, João; Pais, Alberto A. C. C.

doi:10.1016/j.canlet.2018.04.039

Cited by 51 publications

(40 citation statements)

References 101 publications

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“…Drug repurposing is a strategy to safely accelerate discovery of new cancer treatments (reviewed specifically for glioblastoma in Basso, Miranda, Sousa, Pais, & Vitorino, ; Seliger & Hau, ). Cancer generally and glioblastoma specifically use pre‐existing physiological pathways of growth, anti‐apoptosis, and cell migration, albeit subverted and dysregulated to generate malignancy.…”

Section: Introductionmentioning

confidence: 99%

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Bcl‐2/Bcl‐xL inhibition predominantly synergistically enhances the anti‐neoplastic activity of a low‐dose CUSP9 repurposed drug regime against glioblastoma

Halatsch¹,

Kast²,

Dwucet³

et al. 2019

British J Pharmacology

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Background and Purpose Drug repurposing represents a promising approach to safely accelerate the clinical application of therapeutics with anti‐cancer activity. In this study, we examined whether inhibition of the anti‐apoptotic Bcl‐2 family proteins Bcl‐2 and Bcl‐xL enhances the biological effects of the repurposed CUSP9 regimen in an in vitro setting of glioblastoma. Experimental Approach We applied 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromide assays to assess cellular proliferation. Annexin V/propidium iodide and tetramethylrhodamine, ethyl ester staining were used to examine apoptosis. Western blotting, RT‐PCR, and specific knockdown experiments using siRNA were employed to examine molecular mechanisms of action. Key Results Bcl‐2/Bcl‐xL inhibition exerted synergistic anti‐proliferative effects across established, primary cultured, and stem‐like glioblastoma cells when combined with CUSP9 which had been reduced to only one tenth of its proposed original concentration (CUSP9‐LD). The combination treatment also led to enhanced apoptosis with loss of mitochondrial membrane potential and activation of caspases. On the molecular level, CUSP9‐LD counteracted ABT263‐mediated up‐regulation of Mcl‐1. Silencing of Mcl‐1 enhanced ABT263‐mediated apoptosis which indicates that down‐regulation of Mcl‐1 is crucial for the induction of cell death by the combination treatment. Conclusion and Implications These data suggest that Bcl‐2/Bcl‐xL inhibition enhances the susceptibility of glioblastoma cells towards CUSP9, allowing dramatic dose reduction and potentially decreased toxicity when applied clinically. A clinical trial involving the original CUSP doses (CUSP9v3) is currently ongoing in our institution (NCT02770378). The Bcl‐2/Bcl‐xL inhibitor ABT263 is in clinical trials and might represent a valuable adjunct to the original CUSP.

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Section: Introductionmentioning

confidence: 99%

“…Drug repurposing is a strategy to safely accelerate discovery of new cancer treatments (reviewed specifically for glioblastoma in Basso, Miranda, Sousa, Pais, & Vitorino, 2018;Seliger & Hau, 2018).…”

Section: Introductionmentioning

confidence: 99%

Bcl‐2/Bcl‐xL inhibition predominantly synergistically enhances the anti‐neoplastic activity of a low‐dose CUSP9 repurposed drug regime against glioblastoma

Halatsch¹,

Kast²,

Dwucet³

et al. 2019

British J Pharmacology

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“… 21 Nevertheless, the recurrent rates still remain very high, and the primary and secondary drug resistance of GBMs is the main cause of postoperative recurrence and death. 22 Currently, TMZ is the first choice among anti-GBM drugs, 23 while the data from clinics reveals that the initial effective rate of TMZ is about 50% for GBMs, and the frequency of secondary drug resistance is about 35%, 24 resulting in the failure of GBM chemotherapy. Given the lack of newly designed anti-GBM drugs, it is in urgent need to explore a safer and more effective approach to improve the sensitivity and even to reverse TMZ resistance of GBM cells.…”

Section: Discussionmentioning

confidence: 99%

<p>Synergistic Effects of Resveratrol and Temozolomide Against Glioblastoma Cells: Underlying Mechanism and Therapeutic Implications</p>

Liu

Xue

et al. 2020

CMAR

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Purpose Temozolomide (TMZ) is a commonly used anti-glioblastoma (GBM) drug. However, glioblastoma cells frequently show primary and acquired resistance to TMZ. As a promising anti-GBM candidate, resveratrol (Res) faces the similar problem as TMZ. Although resveratrol combined with TMZ (Res/TMZ) has been reported to be used to treat GBMs, it remains unclear whether this combination is broad-spectrum for all glioma cells until now, especially for GBM cells/cases with dual drug resistance. The study aimed to evaluate the synergistic effects of resveratrol and TMZ against GBMs and identify the underlying mechanisms. Materials and Methods Drug sensitivities of rat RG-2, human LN-18 and LN-428 cell lines and effectiveness of Res/TMZ combinations were investigated via multiple experimental methods. O 6 -methylguanine-DNA methyltransferase (MGMT) was observed by Western blotting and immunocytochemistry (ICC). Transducer and activator of transcription 3 (STAT3) signaling pathway and expression changes of STAT3 -related gene were detected to explore the possible synergistic mechanism. Results One hundred micromolar resveratrol and 500 μM TMZ inhibited the growth of RG-2 cells and the low-dose combination (25 μM/250 μM) showed similar suppressive effects. LN-18 and, especially, LN-428 cells were neither sensitive to 100 μM resveratrol nor to 500 μM TMZ, while their growth was suppressed by combination of 75 μM Res/750 μM TMZ with the suppressive rates of 62.5% and 28.6% and apoptosis rates of 11.9% and 7.4%, respectively. Resveratrol had regulatory effect on the expression of MGMT and it could significantly down-regulate MGMT overexpression caused by TMZ. In addition, STAT3/Bcl-2/survivin signaling pathway was also remarkably inhibited in Res/TMZ-treated GBM cells. Conclusion Our results demonstrated synergistic effects of Res/TMZ on RG-2 cells and their bilaterally sensitizing effects to LN-18 and LN-428 cells. Frequent upregulation of MGMT and activation of STAT3 are the unfavorable factors for the treatment of GBMs and they may be the potential targets of Res/TMZ therapy.

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“…Our data suggest that the currently approved CNS drugs, sertraline, chlorprothixene, and chlorpromazine are likely to have polypharmacological activity against the mSin3B PAH1 domain, which binds to REST/NRSF, whose dysregulation is related to glioblastoma, Huntington’s disease, and neuropathic pain in addition to medulloblastoma. Several studies have suggested that sertraline or chlorpromazine is effective against glioblastoma, either when used alone or when used as combinatorial chemotherapy with other drugs 55 – 60 . Although previous studies have proposed other mechanisms of tumor suppression by sertraline or chlorpromazine, our present findings may provide new clues for clinical research on sertraline or chlorpromazine against glioblastoma.…”

Section: Discussionmentioning

confidence: 99%

Sertraline, chlorprothixene, and chlorpromazine characteristically interact with the REST-binding site of the corepressor mSin3, showing medulloblastoma cell growth inhibitory activities

Kurita

Hirao

Nakano

et al. 2018

Sci Rep

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Dysregulation of repressor-element 1 silencing transcription factor REST/NRSF is related to several neuropathies, including medulloblastoma, glioblastoma, Huntington’s disease, and neuropathic pain. Inhibitors of the interaction between the N-terminal repressor domain of REST/NRSF and the PAH1 domain of its corepressor mSin3 may ameliorate such neuropathies. In-silico screening based on the complex structure of REST/NRSF and mSin3 PAH1 yielded 52 active compounds, including approved neuropathic drugs. We investigated their binding affinity to PAH1 by NMR, and their inhibitory activity toward medulloblastoma cell growth. Interestingly, three antidepressant and antipsychotic medicines, sertraline, chlorprothixene, and chlorpromazine, were found to strongly bind to PAH1. Multivariate analysis based on NMR chemical shift changes in PAH1 residues induced by ligand binding was used to identify compound characteristics associated with cell growth inhibition. Active compounds showed a new chemo-type for inhibitors of the REST/NRSF-mSin3 interaction, raising the possibility of new therapies for neuropathies caused by dysregulation of REST/NRSF.

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Repurposing drugs for glioblastoma: From bench to bedside

Cited by 51 publications

References 101 publications

Bcl‐2/Bcl‐xL inhibition predominantly synergistically enhances the anti‐neoplastic activity of a low‐dose CUSP9 repurposed drug regime against glioblastoma

Bcl‐2/Bcl‐xL inhibition predominantly synergistically enhances the anti‐neoplastic activity of a low‐dose CUSP9 repurposed drug regime against glioblastoma

<p>Synergistic Effects of Resveratrol and Temozolomide Against Glioblastoma Cells: Underlying Mechanism and Therapeutic Implications</p>

Sertraline, chlorprothixene, and chlorpromazine characteristically interact with the REST-binding site of the corepressor mSin3, showing medulloblastoma cell growth inhibitory activities

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