Acquired Resistance to Temozolomide in Glioma Cell Lines: Molecular Mechanisms and Potential Translational Applications

Zhang, Jihong; Stevens, Malcolm F. G.; Laughton, Charles A.; Madhusudan, Srinivasan; Bradshaw, Tracey D.

doi:10.1159/000306139

Cited by 96 publications

(86 citation statements)

References 75 publications

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“…MGMT expression in GBM occurs in approximately 40% to 50% of patients with GBM, yet temozolomide resistance is almost universal, demonstrating that other mechanisms of temozolomide resistance are operating (17,45,46). MMR deficiencies are also documented in recurrent patients with GBM (19,20,47). As much as 25% of recurrent GBMs exhibit MMR deficiencies (48).…”

Section: Discussionmentioning

confidence: 99%

“…Another mechanism of temozolomide resistance involved the base excision repair (BER) pathway. This pathway consists of several DNA repair proteins that cooperate in the removal of damaged or inappropriate DNA bases, such as N 7 -meG (20). 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).…”

Section: Introductionmentioning

confidence: 99%

“…If PARP activity is inhibited, these single-stranded DNA breaks become double-strand breaks leading to induction of cell death. Thus, PARP contributes to temozolomide resistance (20), and inhibition of PARP enhances temozolomide-induced cytotoxicity.…”

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: Discussionmentioning

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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“…The mechanism of action of TMZ in gliomas is as follows (11): TMZ is degraded to 5-(3-methyl-1-triazeno) imidazole-4-carboxamide and then to methylhydrazine, which then effectively methylates DNA to generate three main adducts, N7-methylguanine (70%), N3-methyladenine (9%) and O6-methylguanine (O6-me-G; 6%) (27). The generation of O6-me-G is the main cause of the cytotoxic effects of TMZ.…”

Section: Somatic Msh6 Mutations Glioma Recurrence and Drug Resistancementioning

confidence: 99%

Association of MSH6 mutation with glioma susceptibility, drug resistance and progression

Xie

Huang

Zhang

et al. 2016

Molecular and Clinical Oncology

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Abstract. MutS homolog 6 (MSH6) is one of the mismatch repair proteins and is encoded by the MSH6 gene, which is located on chromosome 2 and is 23,806 bp in length, including 10 exons and 83 untranslated regions. The MSH6 protein consists of 1,358 amino acid residues and forms a heterodimer with another mismatch repair protein, MSH2. The MSH2-MSH6 heterodimeric complex is able to recognize base-base substitution and single-base insertion/deletion mismatches. Germline mutations of MSH6 lead to high susceptibility to glioma, as well as a number of benign or malignant tumors in other organs. However, somatic MSH6 mutations are not associated with susceptibility to glioma. Somatic MSH6 mutations usually follow temozolomide treatment and result in resistance to temozolomide. Subsequently, MSH6 mutations cause a hypermutation in the glioma cell genome, which may accelerate tumor progression. Contents1. Introduction 2. Genetic location and function of MSH6 3. Germline MSH6 mutations and cancer susceptibility 4. Somatic MSH6 mutations, glioma recurrence and drug resistance 5. MSH6 mutations lead to tumor genome hypermutation IntroductionGlioma is the most frequent malignant brain tumor in adults. This tumor is characterized by diffuse infiltration of the brain and frequent local recurrence. A malignant tumor is considered to be the result of an accumulation of gene mutations, and tumor progression is driven by additional mutations (1). DNA is constantly exposed to biological, physical and chemical damage that may result in gene mutations; the DNA mismatch repair (MMR) system is responsible for repairing DNA damage. As a result, gene mutations are significantly more frequent in MMR-deficient cells (2,3). Theoretically, mutations in the MMR system may cause additional mutations in numerous other genes, initiating a cascade of mutations throughout the cancer genome. Some of these mutations may confer selective advantages, which enable the mutated cells to proliferate and achieve clonal dominance (4). Growing evidence indicates that a deficiency of MMR genes is associated with the recurrence and drug resistance of glioma. Candidate genes of interest include mutL homolog (MLH)1, mutS homolog (MSH)2 and MSH6 (4,5). In particular, MSH6 mutations are considered to play an important role in the recurrence of glioma, acquired resistance to alkylating agents and genome instability (3,6,7). The aim of the present study was to review the association between MSH6 mutations and glioma. Genetic location and function of MSH6Mismatches inevitably occur during DNA replication. Prokaryotic as well as eukaryotic organisms are equipped with enzymatic systems to repair these mismatches. The bacterial MutHLS system repairs single-base mismatches and small insertion/deletions. Eukaryotic cells possess respective counterpart enzymes to repair mismatches. In yeast, mammalian cells and other organisms, the MMR systems are similar to the prokaryotic MutHLS system, and are therefore named MSHs and MLHs (8). Certain MMR proteins have unique functions...

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Anticancer Therapeutics

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Acquired Resistance to Temozolomide in Glioma Cell Lines: Molecular Mechanisms and Potential Translational Applications

Cited by 96 publications

References 75 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

Association of MSH6 mutation with glioma susceptibility, drug resistance and progression

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