Identification of repaglinide as a therapeutic drug for glioblastoma multiforme

Xiao, Zui Xuan; Chen, Ruo Qiao; Hu, Dian; Xie, Xiao Qiang; Shang, Yu; Chen, Xiao Qian

doi:10.1016/j.bbrc.2017.04.157

Cited by 28 publications

(21 citation statements)

References 21 publications

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“…It may also suggest an important glioma therapeutic strategy by drugs. Indeed, in glioma cells from the C57/GL261 orthotopic glioma model, we found that repaglinide significantly reduced PD-L1 expression, which correlates with the increase of TIL and the increase of survival time of mice (Xiao et al, 2017). These evidence suggest that targeting glioma PD-L1 directly by drugs or RNA interference might be an effective therapy for glioma.…”

Section: The Oncogenic Roles Of Endogenous Pd-l1 As a Signaling Proteinmentioning

confidence: 93%

The Prognostic and Therapeutic Value of PD-L1 in Glioma

et al. 2019

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Glioma is the most common type of primary brain tumors. After standard treatment regimen (surgical section, radiotherapy and chemotherapy), the average survival time remains merely around 14 months for glioblastoma (grade IV glioma). Recent immune therapy targeting to the immune inhibitory checkpoint axis, i.e., programmed cell death protein 1 (PD-1) and its ligand PD-L1 (i.e., CD274 or B7-H1), has achieved breakthrough in many cancers but still not in glioma. PD-L1 is considered a major prognostic biomarker for immune therapy in many cancers, with anti-PD-1 or anti-PD-L1 antibodies being used. However, the expression and subcellular distribution of PD-L1 in glioma cells exhibits great variance in different studies, severely impairing PD-L1's value as therapeutic and prognostic biomarker in glioma. The role of PD-L1 in modulating immune therapy is complicated. In addition, endogenous PD-L1 plays tumorigenic roles in glioma development. In this review, we summarize PD-L1 mRNA expression and protein levels detected by using different methods and antibodies in human glioma tissues in all literatures, and we evaluate the prognostic value of PD-L1 in glioma. We also summarize the relationships between PD-L1 and immune cell infiltration in glioma. The mechanisms regulating PD-L1 expression and the oncogenic roles of endogenous PD-L1 are discussed. Further, the therapeutic results of using anti-PD-1/PD-L1 antibodies or PD-L1 knockdown are summarized and evaluated. In summary, current results support that PD-L1 is not only a prognostic biomarker of immune therapy, but also a potential therapeutic target for glioma.

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Section: The Oncogenic Roles Of Endogenous Pd-l1 As a Signaling Proteinmentioning

confidence: 93%

The Prognostic and Therapeutic Value of PD-L1 in Glioma

et al. 2019

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“…Regarding its potential use in cancer, RPG was identified as a putative new drug for the treatment of glioblastoma multiforme by a Connectivity Map screen. RPG inhibited the proliferation and migration of glioblastoma multiforme cells and in vivo experiments revealed that RPG prolonged the median survival time of mice bearing orthotopic glioma [49]. However, the detailed mechanism of how RPG affects cancer cells has not been described so far.…”

Section: Discussionmentioning

confidence: 99%

Repaglinide Silences the FOXO3/Lumican Axis and Represses the Associated Metastatic Potential of Neuronal Cancer Cells

Salcher

Spoden

Huber

et al. 2019

Cells

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The transcription factor FOXO3 is associated with poor outcome in high-stage neuroblastoma (NB), as it facilitates chemoprotection and tumor angiogenesis. In other tumor entities, FOXO3 stimulates metastasis formation, one of the biggest challenges in the treatment of aggressive NB. However, the impact of FOXO3 on the metastatic potential of neuronal tumor cells remains largely unknown. In the present study, we uncover the small leucine-rich proteoglycan family member lumican (LUM) as a FOXO3-regulated gene that stimulates cellular migration in NB. By a drug-library screen we identified the small molecular weight compound repaglinide (RPG) as a putative FOXO3 inhibitor. Here, we verify that RPG binds to the FOXO3-DNA-binding-domain (DBD) and thereby silences the transcriptional activity of FOXO3. Consistent with the concept that the FOXO3/LUM axis enhances the migratory capacity of aggressive NB cells, we demonstrate that stable knockdown of LUM abrogates the FOXO3-mediated increase in cellular migration. Importantly, FOXO3 inhibition by RPG represses the binding of FOXO3 to the LUM promoter, inhibits FOXO3-mediated LUM RNA and protein expression, and efficiently abrogates FOXO3-triggered cellular “wound healing” as well as spheroid-based 3D-migration. Thus, silencing the FOXO3/LUM axis by the FDA-approved compound RPG represents a promising strategy for novel therapeutic interventions in NB and other FOXO3-dependent tumors.

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“…It is an oral medication used in addition to diet and exercise to control postprandial glucose excursions for the treatment of TIIDM. It promotes the early release of insulin from the pancreas beta-islet cells by closing ATP-dependent potassium channels in the membrane of beta cells (Xiao et al, 2017 ). This results in depolarization and calcium influx to induce insulin secretion.…”

Section: Non-psychiatric Drugsmentioning

confidence: 99%

“…Repaglinide has been reported to kill hepatic, breast, and cervical carcinoma cells (Xiao et al, 2017 ). Xiao et al first identified repaglinide as a potential candidate in GBM and verified that in vitro and in vivo .…”

Section: Non-psychiatric Drugsmentioning

confidence: 99%

“…Xiao et al first identified repaglinide as a potential candidate in GBM and verified that in vitro and in vivo . Other than its ability to inhibit proliferation and migration of GBM cells in vitro , GBM-bearing mice treated with repaglinide also survive longer (Xiao et al, 2017 ). The authors postulated the effects seen were via inducing apoptosis, repressing autophagy, or immune-activation.…”

Section: Non-psychiatric Drugsmentioning

confidence: 99%

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Drug Repositioning in Glioblastoma: A Pathway Perspective

et al. 2018

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Glioblastoma multiforme (GBM) is the most malignant primary adult brain tumor. The current standard of care is surgical resection, radiation, and chemotherapy treatment, which extends life in most cases. Unfortunately, tumor recurrence is nearly universal and patients with recurrent glioblastoma typically survive <1 year. Therefore, new therapies and therapeutic combinations need to be developed that can be quickly approved for use in patients. However, in order to gain approval, therapies need to be safe as well as effective. One possible means of attaining rapid approval is repurposing FDA approved compounds for GBM therapy. However, candidate compounds must be able to penetrate the blood-brain barrier (BBB) and therefore a selection process has to be implemented to identify such compounds that can eliminate GBM tumor expansion. We review here psychiatric and non-psychiatric compounds that may be effective in GBM, as well as potential drugs targeting cell death pathways. We also discuss the potential of data-driven computational approaches to identify compounds that induce cell death in GBM cells, enabled by large reference databases such as the Library of Integrated Network Cell Signatures (LINCS). Finally, we argue that identifying pathways dysregulated in GBM in a patient specific manner is essential for effective repurposing in GBM and other gliomas.

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Identification of repaglinide as a therapeutic drug for glioblastoma multiforme

Cited by 28 publications

References 21 publications

The Prognostic and Therapeutic Value of PD-L1 in Glioma

The Prognostic and Therapeutic Value of PD-L1 in Glioma

Repaglinide Silences the FOXO3/Lumican Axis and Represses the Associated Metastatic Potential of Neuronal Cancer Cells

Drug Repositioning in Glioblastoma: A Pathway Perspective

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