Inhibition of NF-κB Signaling Ablates the Invasive Phenotype of Glioblastoma

Westhoff, Mike‐Andrew; Zhou, Shaoxia; Nonnenmacher, Lisa; Karpel‐Massler, Georg; Jennewein, Carla; Schneider, Matthias; Halatsch, Marc‐Eric; Carragher, Neil O.; Baumann, Bernd; Krause, Alexander; Simmet, Thomas; Bachem, Max G.; Wirtz, Christian Rainer; Debatin, Klaus‐Michael

doi:10.1158/1541-7786.mcr-13-0435-t

Cited by 62 publications

(80 citation statements)

References 45 publications

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“…These micrometastatic deposits may be a major cause of recurrence in glioma. Micrometastases are difficult to detect using conventional methods, such as imaging and clinical pathology (14). The malignant tumor cells of micrometastatic deposits may spread and survive in the lymphatic circulatory system, blood, bone marrow, various tissues and organs, resulting in numerous relevant clinical manifestations (15).…”

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confidence: 99%

Expression of TYMS in lymph node metastasis from low-grade glioma

Ding

Gao

et al. 2015

Oncology Letters

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Abstract. The aim of the present study was to investigate the expression of thymidylate synthase (TYMS) in the primary foci and metastatic lymph nodes of low-grade glioma, and to analyze the function of TYMS in the lymph node metastases from low-grade glioma. The study included 93 cases of surgically resected and pathologically confirmed low-grade glioma, form patients treated at Huaihe Hospital of Henan University (Kaifeng, China). The following clinical data was obtained from each patient: Gender, age, subjective symptoms (dizziness, headache, a feeling of pressure in the head, etc.), site of disease, tumor type, pathological stage, degree of differentiation and lymph node involvement. The surgically resected gliomas and dissected cervical lymph nodes were immunohistochemically stained, and DNA was extracted from the tumor and lymph node tissues samples for polymerase chain reaction sequencing and amplification. The expression of TYMS in the primary foci and metastatic lymph nodes of low-grade glioma was examined. Additionally, the association between pathological features and the postoperative survival rate of the patients was analyzed. The primary lesions of all 93 cases exhibited positive TYMS expression and 43/157 (27.39%) lymph nodes exhibited positive TYMS expression. Factors that significantly influenced the postoperative survival rate of the patients, included the metastasis of the cervical lymph nodes (P<0.01), the number of dissected cervical lymph nodes (P<0.01) and the degree of differentiation (P<0.05). The metastasis of the cervical lymph nodes was the only independent risk factor affecting postoperative disease-free survival. The risk of recurrence in patients with metastasis of the cervical lymph nodes was 6.3-fold higher than in those without metastasis (P<0.01). Thus, the results of the present study provide a theoretical basis for accurately predicting the prognosis of patients with low-grade malignant brain glioma, reducing the conjecture involved in selecting postoperative treatment strategies and improving therapeutic efficacy.

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confidence: 99%

Expression of TYMS in lymph node metastasis from low-grade glioma

Ding

Gao

et al. 2015

Oncology Letters

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“…Although the anticancer mechanisms of DSF are still not well-understood (22), published data indicate that the cytotoxicity of DSF is enhanced in the presence of copper (14,15,23). DSF chelates bivalent metals such as copper (Cu) and zinc (Zn) to form DSF metal complexes that inhibit proteasome activity and block the degradation of IkB and NFkB nuclear translocation (24)(25)(26). In the clinical situation, DSF combined with zinc gluconate has resulted in remission in a melanoma patient with liver metastasis (27).…”

Section: Introductionmentioning

confidence: 99%

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

Lun

Wells

Grinshtein

et al. 2016

Clinical Cancer Research

163

119

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Purpose: Glioblastoma is one of the most lethal cancers in humans, and with existing therapy, survival remains at 14.6 months. Current barriers to successful treatment include their infiltrative behavior, extensive tumor heterogeneity, and the presence of a stem-like population of cells, termed brain tumor-initiating cells (BTIC) that confer resistance to conventional therapies.Experimental Design: To develop therapeutic strategies that target BTICs, we focused on a repurposing approach that explored already-marketed (clinically approved) drugs for therapeutic potential against patient-derived BTICs that encompass the genetic and phenotypic heterogeneity of glioblastoma observed clinically.Results: Using a high-throughput in vitro drug screen, we found that montelukast, clioquinol, and disulfiram (DSF) were cytotoxic against a large panel of patient-derived BTICs. Of these compounds, disulfiram, an off-patent drug previously used to treat alcoholism, in the presence of a copper supplement, showed low nanomolar efficacy in BTICs including those resistant to temozolomide and the highly infiltrative quiescent stem-like population. Low dose DSF-Cu significantly augmented temozolomide activity in vitro, and importantly, prolonged in vivo survival in patient-derived BTIC models established from both newly diagnosed and recurrent tumors. Moreover, we found that in addition to acting as a potent proteasome inhibitor, DSF-Cu functionally impairs DNA repair pathways and enhances the effects of DNA alkylating agents and radiation. These observations suggest that DSF-Cu inhibits proteasome activity and augments the therapeutic effects of DNA-damaging agents (temozolomide and radiation).Conclusions: DSF-Cu should be considered as an adjuvant therapy for the treatment of patients with glioblastoma in both newly diagnosed and recurrent settings.

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“…These protect glioblastoma stem cells from detrimental influences, such as anoikis, and provide a route along where glioblastoma stem cells can transverse the brain. 111 Recent data clearly indicate that established cell lines used as experimental surrogates for glioblastoma poorly reflect the in vivo situation in terms of gene and protein expression. 112,113 Furthermore, these cell lines also lack some key features of glioblastoma when used in orthotopic animal models; no micrometastasis can be observed when using U87MG cells, one of the few cell lines that are actually tumorigenic when used in xenotransplants.…”

Section: N-acetyl-l-cysteinementioning

confidence: 99%

Cancer stem cells: The potential role of autophagy, proteolysis, and cathepsins in glioblastoma stem cells

et al. 2017

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One major obstacle in cancer therapy is chemoresistance leading to tumor recurrence and metastasis. Cancer stem cells, in particular glioblastoma stem cells, are highly resistant to chemotherapy, radiation, and immune recognition. In case of immune recognition, several survival mechanisms including, regulation of autophagy, proteases, and cell surface major histocompatibility complex class I molecules, are found in glioblastoma stem cells. In different pathways, cathepsins play a crucial role in processing functional proteins that are necessary for several processes and proper cell function. Consequently, strategies targeting these pathways in glioblastoma stem cells are promising approaches to interfere with tumor cell survival and will be discussed in this review.

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Inhibition of NF-κB Signaling Ablates the Invasive Phenotype of Glioblastoma

Cited by 62 publications

References 45 publications

Expression of TYMS in lymph node metastasis from low-grade glioma

Expression of TYMS in lymph node metastasis from low-grade glioma

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

Cancer stem cells: The potential role of autophagy, proteolysis, and cathepsins in glioblastoma stem cells

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