Molecular mechanisms of temozolomide resistance in glioblastoma multiforme

Johannessen, Tor‐Christian; Bjerkvig, Rolf

doi:10.1586/era.12.37

Cited by 113 publications

(96 citation statements)

References 78 publications

(39 reference statements)

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“…MGMT overexpression is thus far the best described mechanism of temozolomide resistance in patients with glioma (23). Therefore, the relationship between MGMT status and sensitivity to NEO212 was examined.…”

Section: Neo212 Is Cytotoxic For Mgmt-positive Glioma Cellsmentioning

confidence: 99%

“…Once these methyl groups are removed, the cells replicate and survive; therefore, relatively high levels of these BER proteins are responsible for temozolomide resistance (21,22). Thus, low levels of BER proteins result in cytotoxicity, but overexpression of these proteins is protective and induces temozolomide resistance (23). PARP cooperates with the BER system to ensure genomic stability by repairing single-stranded DNA breaks (23,24).…”

Section: Introductionmentioning

confidence: 99%

“…Thus, low levels of BER proteins result in cytotoxicity, but overexpression of these proteins is protective and induces temozolomide resistance (23). PARP cooperates with the BER system to ensure genomic stability by repairing single-stranded DNA breaks (23,24). If PARP activity is inhibited, these single-stranded DNA breaks become double-strand breaks leading to induction of cell death.…”

Section: Introductionmentioning

confidence: 99%

“…As is apparent from several studies, there is a wide variety of mechanisms causing temozolomide resistance (20,23). The major problem in identifying potential targets to eliminate temozolomide-resistant cells is that there are multiple pathways of temozolomide resistance.…”

Section: Introductionmentioning

confidence: 99%

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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

Cho¹,

Wang²,

Jhaveri³

et al. 2014

Molecular Cancer Therapeutics

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Patients with glioblastoma multiforme (GBM), a malignant primary brain tumor, inevitably develop resistance to standard-of-care chemotherapy, temozolomide. This study explores the effects of the novel agent NEO212, a conjugate of temozolomide to perillyl alcohol, on temozolomide-resistant gliomas. NEO212 was tested for cytotoxic activity on three human temozolomide-resistant glioma cell lines, which were resistant to temozolomide based on overexpression of the base excision repair (BER) pathway, mismatch repair (MMR) deficiency, or overexpression of O 6 methyl-guanine-DNA methyltransferase (MGMT). BER expression was evaluated by Western blotting and PARP activity. MMR deficiency was determined by Western blotting and microsatellite instability. MGMT overexpression was evaluated by Western blotting and O 6 -benzylguanine (O 6 BG) inhibition. For in vivo evaluation of NEO212, temozolomide-resistant glioma cells were implanted into immune-incompetent mice, and NEO212 was administered. NEO212, at equimolar concentrations of temozolomide, was more cytotoxic for temozolomideresistant cells than temozolomide and not toxic to normal cells. NEO212-induced cell death in temozolomide-resistant glioma cells was independent of such mechanisms of resistance as high levels of MGMT, MMR deficiencies, or overexpression of BER proteins. NEO212 functions as a DNA alkylating agent, similar to temozolomide; however, this novel conjugate is unique for it may induce endoplasmic reticulum (ER) stress and inhibits autophagy. In vivo studies show that NEO212 reduces intracranial tumor growth and increases animal survival without significant toxicity. These results demonstrate that NEO212 is an effective drug against malignant gliomas that can be used for a broad range of newly diagnosed and temozolomide-resistant gliomas.

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Section: Neo212 Is Cytotoxic For Mgmt-positive Glioma Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Cho¹,

Wang²,

Jhaveri³

et al. 2014

Molecular Cancer Therapeutics

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show abstract

“…Although TMZ can significantly prolong survival on average, only 45% of patients with newly diagnosed GBM gain substantial benefits from TMZ (6). Furthermore, even in cases in which the tumor responds well to initial treatment and appears to have disappeared on followup, recurrence is common and fatal in the middle of treatment or 1-2 y after completion of the treatment in most cases (7,8).…”

mentioning

confidence: 99%

In vivo chemical exchange saturation transfer imaging allows early detection of a therapeutic response in glioblastoma

Sagiyama

Mashimo

Togao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

175

156

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Significance The prognosis and management of patients with glioma is vastly different depending on whether one detects tumor progression or treatment effects. Although the gold standard in the evaluation of treatment efficacy involves MRI, the currently available imaging methods often do not suffice to make the final decision. Our study demonstrated that amide proton transfer (APT) imaging, one subset of chemical exchange saturation transfer imaging, can detect molecular signals in glioma induced by short-term chemotherapy with temozolomide. These molecular events precede morphologic changes. The APT signal did not decrease in tumors resistant to chemotherapy. APT imaging may provide a useful prognostic biomarker of treatment response or tumor progression in glioma.

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A study of embryonic stem cell‐related proteins in human astrocytomas: Identification of Nanog as a predictor of survival

Elsir

Edqvist

Carlson

et al. 2013

Intl Journal of Cancer

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Recent studies suggest that the regulatory networks controlling the functions of stem cells during development may be abnormally active in human cancers. An embryonic stem cell (ESC) gene signature was found to correlate with a more undifferentiated phenotype of several human cancer types including gliomas, and associated with poor prognosis in breast cancer. In the present study, we used tissue microarrays of 80 low-grade (WHO Grade II) and 98 high-grade human gliomas (WHO Grades III and IV) to investigate the presence of the ESC-related proteins Nanog, Klf4, Oct4, Sox2 and c-Myc by immunohistochemistry. While similar patterns of co-expressed proteins between low-and high-grade gliomas were present, we found up-regulated protein levels of Nanog, Klf4, Oct4 and Sox2 in high-grade gliomas. Survival analysis by Kaplan-Meier analysis revealed a significant shorter survival in the subgroups of low-grade astrocytomas (n 5 42) with high levels of Nanog protein (p 5 0.0067) and of Klf4 protein (p 5 0.0368), in high-grade astrocytomas (n 5 85) with high levels of Nanog (p 5 0.0042), Klf4 (p 5 0.0447), and c-Myc (p 5 0.0078) and in glioblastomas only (n 5 71) with high levels of Nanog (p 5 0.0422) and of c-Myc (p 5 0.0256). In the multivariate model, Nanog was identified as an independent prognostic factor in the subgroups of low-grade astrocytomas (p 5 0.0039), high-grade astrocytomas (p 5 0.0124) and glioblastomas only (p 5 0.0544), together with established clinical variables in these tumors. These findings provide further evidence for the joint regulatory pathways of ESC-related proteins in gliomas and identify Nanog as one of the key players in determining clinical outcome of human astrocytomas.Gliomas are the most common primary tumors of the CNS and are divided into low-grade and high-grade gliomas. 1 Lowgrade gliomas (LGG) in adults are of malignancy Grade II, according to the WHO classification of brain tumors, and commonly occur as astrocytomas, oligodendrogliomas or oligoastrocytomas Grade II. In spite of a relatively favorable prognosis, LGG will eventually transform into high-grade tumors with fatal outcome. 2 High-grade gliomas (HGG) are of Grades III or IV according to the WHO classification. Grade III tumors are referred to as anaplastic gliomas and grade IV is also known as glioblastoma. 1 WHO Grade III tumors of an astrocytic phenotype are highly proliferative, infiltrative tumors but without necrotic areas and/or hyperplastic vasculature, whereas both anaplastic oligodendrogliomas and glioblastomas

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Molecular mechanisms of temozolomide resistance in glioblastoma multiforme

Cited by 113 publications

References 78 publications

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

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

In vivo chemical exchange saturation transfer imaging allows early detection of a therapeutic response in glioblastoma

A study of embryonic stem cell‐related proteins in human astrocytomas: Identification of Nanog as a predictor of survival

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