Combined therapy of temozolomide and ZD6474 (vandetanib) effectively reduces glioblastoma tumor volume through anti-angiogenic and anti-proliferative mechanisms

Jo, Mi-Young; Kim, Young Gyu; Kim, Yonghyun; Lee, Se Jeong; Kim, Mi‐Hyun; Joo, Kyeung Min; Kim, Hyeon Ho; Nam, Do‐Hyun

doi:10.3892/mmr.2012.868

Cited by 9 publications

(4 citation statements)

References 23 publications

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“…The mechanism leading to reduced microvasculature with vandetanib treatment, which could be mediated at least in part by VEGF family receptors, as well as the relative contribution of this effect on the observed reduction in tumor growth, require further study. Similar findings have previously been shown in models of glioblastoma and hepatocellular carcinoma (42, 43). This effect is believed to be mediated by VEGF family receptors and indicates that anti-tumor results seen in luminal breast cancer xenografts with vandetanib treatment could be due to antagonism of multiple receptors.…”

Section: Discussionsupporting

confidence: 90%

Inhibition of RET Increases the Efficacy of Antiestrogen and Is a Novel Treatment Strategy for Luminal Breast Cancer

Spanheimer

Park

Askeland

et al. 2014

Clinical Cancer Research

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Purpose Recent findings suggest that combination treatment with anti-estrogen and anti-RET may offer a novel treatment strategy in a subset of breast cancer patients. We investigated the role of RET in potentiating the effects of anti-estrogen response and examined whether RET expression predicted the ability for tyrosine kinase inhibitor (TKI) to affect ERK1/2 activation in primary breast cancer. Experimental Design Growth response, ERK1/2 activation, Ki-67 and TUNEL were assessed in breast cancer cell lines in vitro and in xenografts with vandetanib and/or tamoxifen. Thirty tumors with matched normal breast tissue were evaluated for RET expression and response to TKI treatment. Results Vandetanib potentiated the inhibitory effect of tamoxifen in hormone responsive (p=0.01) and hormone insensitive (p<0.001) ERα-positive breast cancer cells. Vandetanib significantly repressed tumorigenesis of MCF-7 xenografts (p<0.001), which displayed decreased activation of ERK1/2 and AKT. Vandetanib and tamoxifen reduced the growth of established tumors with a greater effect of dual therapy compared to single agent (p=0.003), with tamoxifen reducing proliferative index and vandetanib inducing apoptosis. In primary breast cancers, RET expression correlated with the ERα-positive subtype. Relative decrease in ERK1/2 phosphorylation with TKI treatment was 42% (p<0.001) in RET-positive tumors vs. 14% (p=ns) in RET-negative tumors. Conclusions Vandetanib potentiated the anti-growth effects of tamoxifen in breast cancer, which was mediated through RET activation. RET predicted response to TKI therapy with minimal effects on ERK1/2 activation in RET-negative tumors. The preclinical data support evaluation of anti-estrogen in combination with TKI as a potential treatment strategy for RET-positive luminal breast cancer.

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Section: Discussionsupporting

confidence: 90%

Inhibition of RET Increases the Efficacy of Antiestrogen and Is a Novel Treatment Strategy for Luminal Breast Cancer

Spanheimer

Park

Askeland

et al. 2014

Clinical Cancer Research

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“…Indeed, TMZ arrests the cell cycle in the G 2 /M phase and reduces the proliferation of U251 and U87MG glioblastoma cells [35,36]. Furthermore, a reduction in the number of PCNA-immunopositive cells was detected in the brain of rodents grafted with C6 or U87MG glioma cells and treated with TMZ [37,38]. Together with those previous data, our PCNA protein expression results corroborate the antiproliferative effect of TMZ in A172 cells, which has not been previously reported.…”

Section: Discussionsupporting

confidence: 90%

Sulfasalazine intensifies temozolomide cytotoxicity in human glioblastoma cells

et al. 2016

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Temozolomide (TMZ) is an alkylating agent used to treat glioblastoma. This tumor type synthesizes the antioxidant glutathione through system X c (-) , which is inhibited by sulfasalazine (SAS). We exposed A172 and T98G human glioblastoma cells to a presumably clinically relevant concentration of TMZ (25 µM) and/or 0.5 mM SAS for 1, 3, or 5 days and assessed cell viability. For both cell lines, TMZ alone did not alter viability at any time point, while the coadministration of TMZ and SAS significantly reduced cell viability after 5 days. The drug combination exerted a synergistic effect on A172 cells after 3 and 5 days. Therefore, this particular lineage was subjected to complementary analyses on the genetic (transcriptome) and functional (glutathione and proliferating cell nuclear antigen (PCNA) protein) levels. Cellular pathways containing differentially expressed genes related to the cell cycle were modified by TMZ alone. On the other hand, SAS regulated pathways associated with glutathione metabolism and synthesis, irrespective of TMZ. Moreover, SAS, but not TMZ, depleted the total glutathione level. Compared with the vehicle-treated cells, the level of PCNA protein was lower in cells treated with TMZ alone or in combination with SAS. In conclusion, our data showed that the association of TMZ and SAS is cytotoxic to T98G and A172 cells, thus providing useful insights for improving TMZ clinical efficacy through testing this novel drug combination. Moreover, the present study not only reports original information on differential gene expression in glioblastoma cells exposed to TMZ and/or SAS but also describes an antiproliferative effect of TMZ, which has not yet been observed in A172 cells.

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“…To investigate the underlying mechanisms of tumor volume reduction in detail, the effects of TMZ and SB on proliferation and apoptosis were investigated. It has already been shown that both TMZ and SB have an inhibitory influence on the proliferation of tumor cells [ 4 , 40 , 41 , 42 , 43 ]. It was therefore interesting to see whether the effects of both substances could potentiate one another.…”

Section: Resultsmentioning

confidence: 99%

Tumor-Associated Microglia/Macrophages as a Predictor for Survival in Glioblastoma and Temozolomide-Induced Changes in CXCR2 Signaling with New Resistance Overcoming Strategy by Combination Therapy

Urbantat

Jelgersma

Brandenburg

et al. 2021

IJMS

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Tumor recurrence is the main challenge in glioblastoma (GBM) treatment. Gold standard therapy temozolomide (TMZ) is known to induce upregulation of IL8/CXCL2/CXCR2 signaling that promotes tumor progression and angiogenesis. Our aim was to verify the alterations on this signaling pathway in human GBM recurrence and to investigate the impact of TMZ in particular. Furthermore, a combi-therapy of TMZ and CXCR2 antagonization was established to assess the efficacy and tolerability. First, we analyzed 76 matched primary and recurrent GBM samples with regard to various histological aspects with a focus on the role of TMZ treatment and the assessment of predictors of overall survival (OS). Second, the combi-therapy with TMZ and CXCR2-antagonization was evaluated in a syngeneic mouse tumor model with in-depth immunohistological investigations and subsequent gene expression analyses. We observed a significantly decreased infiltration of tumor-associated microglia/macrophages (TAM) in recurrent tumors, while a high TAM infiltration in primary tumors was associated with a reduced OS. Additionally, more patients expressed IL8 in recurrent tumors and TMZ therapy maintained CXCL2 expression. In mice, enhanced anti-tumoral effects were observed after combi-therapy. In conclusion, high TAM infiltration predicts a survival disadvantage, supporting findings of the tumor-promoting phenotype of TAMs. Furthermore, the combination therapy seemed to be promising to overcome CXCR2-mediated resistance.

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Combined therapy of temozolomide and ZD6474 (vandetanib) effectively reduces glioblastoma tumor volume through anti-angiogenic and anti-proliferative mechanisms

Cited by 9 publications

References 23 publications

Inhibition of RET Increases the Efficacy of Antiestrogen and Is a Novel Treatment Strategy for Luminal Breast Cancer

Inhibition of RET Increases the Efficacy of Antiestrogen and Is a Novel Treatment Strategy for Luminal Breast Cancer

Sulfasalazine intensifies temozolomide cytotoxicity in human glioblastoma cells

Tumor-Associated Microglia/Macrophages as a Predictor for Survival in Glioblastoma and Temozolomide-Induced Changes in CXCR2 Signaling with New Resistance Overcoming Strategy by Combination Therapy

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