NEO212, Temozolomide Conjugated to Perillyl Alcohol, Is a Novel Drug for Effective Treatment of a Broad Range of Temozolomide-Resistant Gliomas

Cho, Hee‐Yeon; Wang, Weijun; Jhaveri, Niyati; Lee, David Jungpa; Sharma, Natasha; Dubeau, Louis; Schönthal, Axel H.; Hofman, Florence M.; Chen, Thomas C.

doi:10.1158/1535-7163.mct-13-0964

Cited by 50 publications

(51 citation statements)

References 47 publications

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“…Resistant U251 cells are associated with the overexpression of base excision repair proteins. 14 The TMZ R cells were also tested using the long-term colonyformation assay (CFA; Fig. 2D).…”

Section: Results Cytotoxicity Of Qbas For Glioma Cellsmentioning

confidence: 99%

Quinoline-based antimalarial drugs: a novel class of autophagy inhibitors

Golden

Cho²,

Hofman³

et al. 2015

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OBJECT Chloroquine (CQ) is a quinoline-based drug widely used for the prevention and treatment of malaria. More recent studies have provided evidence that this drug may also harbor antitumor properties, whereby CQ possesses the ability to accumulate in lysosomes and blocks the cellular process of autophagy. Therefore, the authors of this study set out to investigate whether CQ analogs, in particular clinically established antimalaria drugs, would also be able to exert antitumor properties, with a specific focus on glioma cells. METHODS Toward this goal, the authors treated different glioma cell lines with quinine (QN), quinacrine (QNX), mefloquine (MFQ), and hydroxychloroquine (HCQ) and investigated endoplasmic reticulum (ER) stress–induced cell death, autophagy, and cell death. RESULTS All agents blocked cellular autophagy and exerted cytotoxic effects on drug-sensitive and drug-resistant glioma cells with varying degrees of potency (QNX > MFQ > HCQ > CQ > QN). Furthermore, all quinoline-based drugs killed glioma cells that were highly resistant to temozolomide (TMZ), the current standard of care for patients with glioma. The cytotoxic mechanism involved the induction of apoptosis and ER stress, as indicated by poly(ADP-ribose) polymerase (PARP) cleavage and CHOP/GADD153. The induction of ER stress and resulting apoptosis could be confirmed in the in vivo setting, in which tumor tissues from animals treated with quinoline-based drugs showed increased expression of CHOP/GADD153, along with elevated TUNEL staining, a measure of apoptosis. CONCLUSIONS Thus, the antimalarial compounds investigated in this study hold promise as a novel class of autophagy inhibitors for the treatment of newly diagnosed TMZ-sensitive and recurrent TMZ-resistant gliomas.

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“…Resistant U251 cells are associated with the overexpression of base excision repair proteins. 14 The TMZ R cells were also tested using the long-term colonyformation assay (CFA; Fig. 2D).…”

Section: Results Cytotoxicity Of Qbas For Glioma Cellsmentioning

confidence: 99%

Quinoline-based antimalarial drugs: a novel class of autophagy inhibitors

Golden

Cho²,

Hofman³

et al. 2015

FOC

Self Cite

149

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“…In this regard, tumor cells use adaptive pathways to circumvent the cellular stress conditions associated with hypoxia, low glucose levels, or chemotherapeutic drug exposure (Li and Lee, 2006; Luo and Lee, 2013). As such, strategies aimed at blocking these adaptations may improve treatment efficacy (Booth et al, 2014; Cho et al, 2014; Ciechomska et al, 2013; Johnson et al, 2014; Liu et al, 2013; Suzuki et al, 2013). While the precise mechanism responsible for ABCG1-mediated suppression of ER stress remains to be elucidated, its potential importance to glioma biology is underscored by preliminary studies demonstrating that high ABCG1 expression correlated with shorter overall survival in patients with glioblastoma of the mesenchymal subtype (Jingqin Luo, unpublished results).…”

Section: Discussionmentioning

confidence: 99%

Mouse Low-Grade Gliomas Contain Cancer Stem Cells with Unique Molecular and Functional Properties

et al. 2015

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Summary The availability of adult malignant glioma stem cells (GSCs) has provided unprecedented opportunities to identify the mechanisms underlying treatment resistance. Unfortunately, there is a lack of comparable reagents for the study of pediatric low-grade glioma (LGG). Leveraging a neurofibromatosis-1 (Nf1) genetically-engineered mouse LGG model, we report the isolation of CD133+ multi-potent low-grade glioma stem cells (LG-GSCs), which generate glioma-like lesions histologically similar to the parent tumor following injection into immunocompetent hosts. In addition, we demonstrate that these LG-GSCs harbor selective resistance to currently-employed conventional and biologically-targeted anti-cancer agents, which reflect the acquisition of new targetable signaling pathway abnormalities. Using transcriptomal analysis to identify additional molecular properties, we discovered that mouse and human LG-GSCs harbor high levels of Abcg1 expression critical for protecting against endoplasmic reticulum (ER) stress-induced mouse LG-GSC apoptosis. Collectively, these findings establish that LGG cancer stem cells have unique molecular and functional properties relevant to brain cancer treatment.

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“…Autophagy has also been described as a mechanism of resistance to TMZ-induced cell death and recent studies have pointed towards up-regulation of the vesicle associated membrane protein 8 (VAMP8) as a potential component in inducing autophagy and TMZ resistance [39]. A novel TMZ analog NEO212, which induces ER stress and blocks autophagy apart from DNA alkylation was recently tested in preclinical studies and found to be promising [40]. …”

Section: Autophagymentioning

confidence: 99%

How to train glioma cells to die: molecular challenges in cell death

2015

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The five-year survival rate for patients with malignant glioma is less than 10%. Despite aggressive chemo/radiotherapy these tumors have remained resistant to almost every interventional strategy evaluated in patients. Resistance to these agents is attributed to extrinsic mechanisms such as the tumor microenvironment, poor drug penetration, and tumoral heterogeneity. In addition, genetic and molecular examination of these tumors has revealed defective apoptotic regulation, enhanced pro-survival autophagy signaling, and a propensity for necrosis that aids in the adaptation to environmental stress and resistance to treatment. The combination of extrinsic and intrinsic hallmarks in glioma contributes to the multifaceted resistance to traditional anti-tumor agents. Here we describe the biology of the disease relevant to therapeutic resistance, with a specific focus on molecular deregulation of cell death pathways. Emerging studies investigating the targeting of these pathways including BH3 mimetics and autophagy inhibitors are being evaluated in both the preclinical and clinical settings are discussed. This review highlights the pathways exploited by glioblastoma cells that drive their hallmark pro-survival predisposition and makes therapy development such a challenge. Keywords glioma; apoptosis; autophagy; necrosis; resistance While primary malignant brain tumors are rare, the 5-year survival for these patients is dismal at approximately 10%. Utilizing the World Health Organization based classification, these tumors are categorized as low-grade (I-II) or high-grade malignant gliomas (III-IV) [1]. Specifically, grade IV glioma or glioblastoma (GBM) [2] are the most common and destructive form of malignant glioma. Headaches, seizures, cognitive and personality changes, gait imbalance, sensory loss, and incontinence are common symptoms and can be dependent on the location of the tumor. Symptomatic management for these patients consists mainly of steroids to relieve neurological symptoms associated with edema and Despite aggressive surgical resection and concurrent chemo/radiotherapy 70% of patients diagnosed with GBM will succumb to the disease within two years. A better understanding of the molecular changes in these malignant cells in response to therapy is necessary to unveil how these malignant cells can survive intense chemo/radiation insult. Recent studies have identified numerous mechanisms by which cells "commit suicide" (Fig. 1) and a better understanding of the mechanisms of cell death exploited by different therapeutics is essential for the rational design of future therapeutic strategies. Here we discuss the current treatment strategies utilized to kill GBM cells, and various cell death mechanisms relevant to glioma destruction and resistance. HHS Public Access ApoptosisApoptosis is perhaps the most well studied form of cellular demise consisting of an energydependent cascade of molecular signaling typically involving the cysteine-dependent aspartate-directed proteases called caspases. Caspase-dep...

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NEO212, Temozolomide Conjugated to Perillyl Alcohol, Is a Novel Drug for Effective Treatment of a Broad Range of Temozolomide-Resistant Gliomas

Cited by 50 publications

References 47 publications

Quinoline-based antimalarial drugs: a novel class of autophagy inhibitors

Quinoline-based antimalarial drugs: a novel class of autophagy inhibitors

Mouse Low-Grade Gliomas Contain Cancer Stem Cells with Unique Molecular and Functional Properties

How to train glioma cells to die: molecular challenges in cell death

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