Drug resistance in brain tumors

Feun, Lynn G.; Savaraj, Niramol; Landy, Howard J.

doi:10.1007/bf01052726

Cited by 59 publications

(44 citation statements)

References 60 publications

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“…In our study, we observed that combined treatment of glioma cells with chemotherapy drug TMZ and CDK6 shRNA significantly inhibited cell growth, which is more effective than single treatment either with TMZ or CDK6 shRNA. The mechanism underlying chemotherapy-resistance of glioma has been intensively studied (18,19,21,22). Many drugresistant genes have been found, which mainly belongs to DNA repair enzymes, small-molecule transmembrane transporters and drug metabolism proteins.…”

Section: Discussionmentioning

confidence: 99%

“…However, the low permeability of drugs across blood-brain barrier reduced drug concentration in cerebral-spinal fluid. On the other hand, glioma cell are resistant to chemotherapy treatment, mainly due to high activity of DNA repair mechanism, tolerance to cell cycle check points, reduced uptake of drug and quick metabolism of drug molecules (18)(19)(20).…”

Section: Enhanced Chemotherapy Effect Of Tmz On Cdk6-knockdown Gliomamentioning

confidence: 99%

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Knockdown of CDK6 enhances glioma sensitivity to chemotherapy

Tao

et al. 2012

Oncol Rep

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Abstract. Chemotherapy is widely used for the treatment of glioma. Given the high resistance of brain neoplasm tissues to chemotherapy, it is important to find new methods to improve the effects of chemotherapy. However, the molecular mechanisms underlying glioma resistance to chemotherapy are largely unknown. Here, we demonstrate that CDK6, a cell cycle regulator, is significantly upregulated in glioma cells, and the increasing expression of CDK6 correlates well with the grades of glioma malignancy. Using shRNA-mediated CDK6 knockdown, we found that the proliferation and survival of tumor cells were dramatically inhibited. Moreover, CDK6 knockdown in the U251 glioma cell line caused significant increase in the apoptosis of U251 cells treated with temozolomide (TMZ). Furthermore, CDK6 knockdown reduced the expression level of drug resistance genes such as MRP and MDR. These data indicate that CDK6 is an important mediator of glioma resistance to chemotherapy. Our findings provide a new strategy for the development of chemotherapy sensitizer. IntroductionGlioma is the most common tumor of the brain and accounts for 45-55% of all brain tumors. Based on histological features (nuclear atypia, mitosis, microvascular enrichment and necrosis) and malignancy, glioma is classified into four grades (1). Grade 1 is innocent and curable with surgical resection; grade 2 is a low grade diffuse glioma and can progress into higher grades; grade 3 and 4 gliomas are malignant and have increased capability to proliferate and invade. The grade 4 glioma, glioblastoma multiforme (GBM), is the most aggressive.Surgical resection is the primary therapy to treat glioma (2). However, surgical removal is very restrictive, thus it is difficult to completely remove diffusive tumor tissues, especially higher grade gliomas. These glioma tissues invade into the white matter or diffuse along the ventricle surface, so other strategies such as chemotherapy are very important to remove cancer cells as completely as possible (3-5). Chemotherapy increases the life of GBM patients. Clinical statistics reveals that, chemotherapy treatment leads to a 15% reduction of mortality, and a 6% increase of 1-more year survival. However, the effect of chemotherapy on glioma is not satisfactory, largely due to three problems. The first problem is the diagnosis of diffusive glioma tissues, which are tiny and grow deep in the brain tissue and are hard to access. The second problem is the blockade of chemotherapy drug by the blood-brain barrier. The third problem is that glioma is highly tolerant under chemotherapy treatment. Understanding the fundamentals, especially the molecular mechanisms, is critical to increase the susceptibility of glioma to chemotherapy.Tumor cells originated from cells with abnormal proliferation and dysregulation of the cell cycle (6,7). Molecular profiling studies showed that the genes controlling cell growth and restricting cell division are silenced, and genes promoting cell proliferation and facilitating cell cycle are overexpressed. M...

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Section: Discussionmentioning

confidence: 99%

Section: Enhanced Chemotherapy Effect Of Tmz On Cdk6-knockdown Gliomamentioning

confidence: 99%

Knockdown of CDK6 enhances glioma sensitivity to chemotherapy

Tao

et al. 2012

Oncol Rep

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“…Pgp, MRP1, MRP2 and MRP3 share the property of transporting common substrates such as vincristine and etoposide, 2 anticancer drugs widely used in the treatment of human brain tumours. 1,9 Today, it seems relevant to question whether MRP1, MRP2 and MRP3 are involved in the MDR phenotype of human cancer cells where they are overexpressed. 6,10,11 In contrast, high MRP5 expression in some lung cancer cell lines is not correlated with the level of resistance of these cell lines against drugs involved in the MDR phenotype such as vincristine or doxorubicin.…”

mentioning

confidence: 99%

Molecular and functional MDR1‐Pgp and MRPs expression in human glioblastoma multiforme cell lines

Declèves

Fajac

Lehmann-Che

et al. 2002

Intl Journal of Cancer

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“…A number of mechanisms may contribute to cellular drug resistance, such as reduced intracellular drug concentrations, rapid inactivation of the drug by induction of certain enzyme systems and increased rate of DNA repair. 1) Dysregulation of apoptosis, a genetically controlled form of cell death, may also be important for drug resistance because the mechanism by which most chemotherapeutic agents induced cell death appeared to be apoptosis. 2) Identification of the gene related to apoptosis and gene products and investigation of the mechanisms of the apoptotic regulation have laid a foundation for the discovery of new drugs.…”

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confidence: 99%

Bcl-2 Up-Regulation and P-p53 Down-Regulation Account for the Low Sensitivity of Murine L929 Fibrosarcoma Cells to Oridonin-Induced Apoptosis

Huang

Li-jun

Tashiro

et al. 2005

Biological & Pharmaceutical Bulletin

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Drug resistance has been a major limitation to chemotherapy. There are many mechanisms that contribute to such resistance. In our study, we subcloned oridonin-sensitive and low sensitive L929 cells and both types of cells grew at almost the same growth rate. The acquired low sensitivity to oridonin-induced apoptosis was associated with Bcl-2 up-regulation and down-regulation of p53 phosphorylation. The p38 inhibitor SB203580 decreased Bcl-2 expression in the low sensitive L929 cells and made the cells more sensitive to oridonin. Moreover, a higher dose of oridonin promoted p53 phosphorylation, increased Bax expression and subsequently induced death of low sensitive L929 cells, however, it had no effect on Bcl-2 expression. The increased Bcl-2/Bax ratio in oridonin low sensitive L929 cells did not inhibit caspase-9 or -3 activation, but suppressed the cleavage of poly (ADP-ribose) polymerase (PARP), indicating the existence of caspase-9 or -3 independent PARP activation. These results indicated that in L929 cells, there was a relationship among the low sensitivity to oridonin, downregulation of p53 phosphorylation and Bcl-2 up-regulation.

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Drug resistance in brain tumors

Cited by 59 publications

References 60 publications

Knockdown of CDK6 enhances glioma sensitivity to chemotherapy

Knockdown of CDK6 enhances glioma sensitivity to chemotherapy

Molecular and functional MDR1‐Pgp and MRPs expression in human glioblastoma multiforme cell lines

Bcl-2 Up-Regulation and P-p53 Down-Regulation Account for the Low Sensitivity of Murine L929 Fibrosarcoma Cells to Oridonin-Induced Apoptosis

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