Re-purposing Chloroquine for Glioblastoma: Potential Merits and Confounding Variables

Weyerhäuser, Patrick; Kantelhardt, Sven R.; Kim, Ella L.

doi:10.3389/fonc.2018.00335

Cited by 61 publications

(53 citation statements)

References 74 publications

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“…U87MG GBM culture. CQ, a well-established clinical antimalarial drug that blocked the general lysosomal function and autophagosome fusion with lysosomes, was previously used for GBM treatment 37,38 . The presence of CQ also prevented LC3-II degradation by lysosomes in the cells and caused an additional increase in LC3-II/ LC3-I ratio in the control and in CBD-treated cells ( Fig.…”

Section: Effects Of a Triple Combination Of Cbd γ-Irradiation And Cmentioning

confidence: 99%

RETRACTED ARTICLE: Inhibition of autophagic flux differently modulates cannabidiol-induced death in 2D and 3D glioblastoma cell cultures

Ivanov

Grabham

et al. 2020

Sci Rep

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Radiotherapy combined with chemotherapy is the major treatment modality for human glioblastoma multiforme (GBM). GBMs eventually relapse after treatment and the average survival of GBM patients is less than two years. There is some evidence that cannabidiol (CBD) can induce cell death and increases the radiosensitivity of GBM by enhancing apoptosis. Beside initiation of death, CBD has been demonstrated as an inducer of autophagy. In the present study, we address the question whether CBD simultaneously induces a protective effect in GBM by upregulating autophagy. Addition of chloroquine that suppressed autophagic flux to 2D GBM cultures increased CBD-induced cell death, presenting proof for the protective autophagy. Blockage of autophagy upregulated radiation-induced cytotoxicity but only modestly affected the levels of cell death in CBD-or CBD/γ-irradiated 3D GBM cultures. Furthermore, CBD enhanced the pro-apoptotic activities of JNK1/2 and MAPK p38 signaling cascades while partially downregulated the pro-survival PI3K-AKT cascade, thereby changing a balance between cell death and survival. Suppression of JNK activation partially reduced CBD-induced cell death in 3D GBM cultures. In contrast, co-treatment of CBD-targeted cells with inhibitors of PI3K-AKT-NF-κB, IKK-NF-κB or JAK2-STAT3 pathways killed surviving GBM cells in both 2D and 3D cultures, potentially improving the therapeutic ratio of GBM. Human glioblastoma multiforme (GBM) is the most lethal primary brain cancer in adults. In the United States alone, approximately 12,000 patients are diagnosed with GBM each year 1. The standard care for GBM includes surgical resection followed by concurrent external beam radiotherapy (with a total dose of 60 Gy) together with temozolomide (TMZ), as a supplemental DNA-methylating agent. It is followed by one year of adjuvant treatment with TMZ 2. While external beam radiation therapy efficiently targets brain tumors, it could be accompanied by severe side effects, such as encephalopathy, strong cognitive and memory deficits 3-8. Despite advances in GBM radiotherapy, outcomes remain poor with a median survival rate of 12-15 months after initial diagnosis 9,10. In the past 10 years, survival in the treatment of this disease did not increase significantly. In spite of intense investigation on the gene drivers of GBM tumorigenesis, targeted therapies against these drivers have remained inefficient 11. Numerous studies in the recent years revealed pronounced cytotoxic effects of cannabinoids [cannabidiol (CBD) and Δ 9-tetrahydrocannabinol (THC)] for GBM in cell culture and experimental animals 12-16. Furthermore, preclinical studies demonstrated that treatment of GBM by combinations of cannabinoids and γ-irradiation or cannabinoids with TMZ was more effective against cancer cells than non-transformed cells in the brain 17-19. To further increase efficiency, specificity, and safety of the treatment, we address in the present study the question whether autophagy could play a protective role in the survival of CBD/γ-irradiation...

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Section: Effects Of a Triple Combination Of Cbd γ-Irradiation And Cmentioning

confidence: 99%

RETRACTED ARTICLE: Inhibition of autophagic flux differently modulates cannabidiol-induced death in 2D and 3D glioblastoma cell cultures

Ivanov

Grabham

et al. 2020

Sci Rep

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“…The prognosis of cancer patients has been linked to the activation status of innate T cells which is the front line of host defense against cancer [115]. Malaria and Chagas disease were found associated with cancer [116][117][118][119]. The relation to Malaria and Chagas disease pathways indicates the lncRNA signature identified from the pan-cancer scenario captures shared characteristics that drive diverse human diseases.…”

Section: Discussionmentioning

confidence: 99%

“…The relation to Malaria and Chagas disease pathways indicates the lncRNA signature identified from the pan-cancer scenario captures shared characteristics that drive diverse human diseases. This may facilitate drug repurposes, for example, Weyerhäuser et al repurposed antimalarial chloroquine for treatment of glioblastoma [119] and Kraus et al used anti-cancer drugs to treat Chagas disease [118]. Functional and tissue studies are needed, however, to determine their exact role in these cellular processes.…”

Section: Discussionmentioning

confidence: 99%

Identification of lncRNA Signature Associated With Pan-Cancer Prognosis

Bao

Wang

et al. 2021

IEEE J. Biomed. Health Inform.

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Long noncoding RNAs (lncRNAs) have emerged as potential prognostic markers in various human cancers as they participate in many malignant behaviors. However, the value of lncRNAs as prognostic markers among diverse human cancers is still under investigation, and a systematic signature based on these transcripts that related to pan-cancer prognosis has yet to be reported. In this study, we proposed a framework to incorporate statistical power, biological rationale, and machine learning models for pan-cancer prognosis analysis. The framework identified a 5-lncRNA signature (ENSG00000206567, PCAT29, ENSG00000257989, LOC388282, and LINC00339) from TCGA training studies (n=1,878). The identified lncRNAs are significantly associated (all P ≤1.48E-11) with overall survival (OS) of the TCGA cohort (n=4,231). The signature stratified the cohort into low-and high-risk groups with significantly distinct survival outcomes (median OS of 9.84 years versus 4.37 years, log-rank P=1.48E-38) and achieved a time-dependent ROC/AUC of 0.66 at 5 years. After routine clinical factors involved, the signature demonstrated better performance for long-term prognostic estimation (AUC of 0.72). Moreover, the signature was further evaluated on two independent external cohorts (TARGET, n=1,122; CPTAC, n=391; National Cancer Institute) which yielded similar prognostic values (AUC of 0.60 and 0.75; logrank P=8.6E-09 and P=2.7E-06). An indexing system was developed to map the 5-lncRNA signature to prognoses of pan-cancer patients. In silico functional analysis indicated that the lncRNAs are associated with common biological processes driving human cancers. The five lncRNAs, especially ENSG00000206567, ENSG00000257989 and LOC388282 that never reported before, may serve as viable molecular targets common among diverse cancers.

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“…We elected to include all trials that could recruit OPGs; however, the vast majority are not focussed on OPGs but on LGG in general. We ensured that [55]. Sirolimus/everolimus First-and second-generation mTOR inhibitors.…”

Section: Limitationsmentioning

confidence: 99%

A systematic review of ongoing clinical trials in optic pathway gliomas

et al. 2020

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Introduction Optic pathway gliomas (OPGs), also known as Visual Pathway Gliomas, are insidious, debilitating tumours. They are most commonly WHO grade 1 pilocytic astrocytomas and frequently occur in patients with neurofibromatosis type 1. The location of OPGs within the optic pathway typically precludes complete resection or optimal radiation dosing, hence outcomes remain poor compared to many other low-grade gliomas. The aim of this systematic review was to formulate a comprehensive list of all current ongoing clinical trials that are specifically looking at clinical care of OPGs in order to identify trends in current research and provide an overview to guide future research efforts. Methods This systematic review was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The Cochrane Controlled Register of Trials (CENTRAL) and ClinicalTrials.gov were searched. Inclusion and exclusion criteria were applied and final results were reviewed. Results 501 clinical trials were identified with the search strategy. All were screened and eligible studies extracted and reviewed. This yielded 36 ongoing clinical trials, 27 of which were pharmacological agents in phase I-III. The remaining trials were a mixture of biological agents, radiation optimisation, diagnostic imaging, surgical intervention, and a social function analysis. Conclusion OPG is a complex multifaceted disease, and advances in care require ongoing research efforts across a spectrum of different research fields. This review provides an update on the current state of research in OPG and summarises ongoing trials.

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Re-purposing Chloroquine for Glioblastoma: Potential Merits and Confounding Variables

Cited by 61 publications

References 74 publications

RETRACTED ARTICLE: Inhibition of autophagic flux differently modulates cannabidiol-induced death in 2D and 3D glioblastoma cell cultures

RETRACTED ARTICLE: Inhibition of autophagic flux differently modulates cannabidiol-induced death in 2D and 3D glioblastoma cell cultures

Identification of lncRNA Signature Associated With Pan-Cancer Prognosis

A systematic review of ongoing clinical trials in optic pathway gliomas

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