MGMT modulates glioblastoma angiogenesis and response to the tyrosine kinase inhibitor sunitinib

Chahal, Manik; Xu, Yaoxian; Lesniak, David; Graham, Kathryn; Famulski, Konrad S.; Christensen, James G.; Aghi, Manish K.; Jacques, Amanda Virtuoso; Murray, David C.; Sabri, Siham; Abdulkarim, Bassam

doi:10.1093/neuonc/noq017

Cited by 77 publications

(61 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It also has been suggested that MGMT has other (nonrepair) functions, as it has been reported to correlate with vascular endothelial growth factor receptors (VEGFRs) expression in vitro (43) and possibly play a role in integrating DNA damage/repair related signals with replication, cell cycle progression and genomic stability (44,45).…”

Section: Introductionmentioning

confidence: 99%

MGMT Inhibition Restores ERα Functional Sensitivity to Antiestrogen Therapy

Bobustuc

Smith

Maddipatla

et al. 2012

Mol Med

View full text Add to dashboard Cite

Antiestrogen therapy resistance remains a huge stumbling block in the treatment of breast cancer. We have found significant elevation of O 6 methylguanine DNA methyl transferase (MGMT) expression in a small sample of consecutive patients who have failed tamoxifen treatment. Here, we show that tamoxifen resistance is accompanied by upregulation of MGMT. Further we show that administration of the MGMT inhibitor, O 6 -benzylguanine (BG), at nontoxic doses, leads to restoration of a favorable estrogen receptor alpha (ERα) phosphorylation phenotype (high p-ERα Ser167/low p-ERα Ser118), which has been reported to correlate with sensitivity to endocrine therapy and improved survival. We also show BG to be a dual inhibitor of MGMT and ERα. . We also show that BG, alone or in combination therapy, curtails the growth of tamoxifen-resistant breast cancer in vitro and in vivo. In tamoxifen-resistant MCF7 breast cancer xenografts, BG alone or in combination treatment causes significant delay in tumor growth. Immunohistochemistry confirms that BG increases p21 cip1/waf1 and p-ERα Ser167 expression and inhibits MGMT, ERα, p-ERα Ser118 and ki-67 expression. Collectively, our results suggest that MGMT inhibition leads to growth inhibition of tamoxifen-resistant breast cancer in vitro and in vivo and resensitizes tamoxifen-resistant breast cancer cells to antiestrogen therapy. These findings suggest that MGMT inhibition may provide a novel therapeutic strategy for overcoming antiestrogen resistance.

show abstract

Section: Introductionmentioning

confidence: 99%

MGMT Inhibition Restores ERα Functional Sensitivity to Antiestrogen Therapy

Bobustuc

Smith

Maddipatla

et al. 2012

Mol Med

View full text Add to dashboard Cite

show abstract

“…Overexpression of dimethylarginine dimethylaminohydrolase 2 was found to increase VEGF mrna expression and enhance tube formation (32). a recent study demonstrated that mGmt modulates GBM angiogenesis, and identified angiogenesis related-genes, including VEGF and its receptors in mGmtpositive GBm cells, demonstrating that VEGF receptors are differentially expressed according to mGmt status (15). Based on these findings, we hypothesized that reduced migration and tube formation in huVEcs may result from metronomic treatment of tmZ which leads to a decreased mGmt expression level, but also that metronomic treatment of tmZ may alter and reconstruct endogenous expression and secretion of VEGF and its receptors in huVEcs.…”

Section: Discussionmentioning

confidence: 98%

“…moreover, clinical research has reported that methylation of the mGmt promoter is useful to predict the responsiveness to alkylating agents (14). Recently, significant inhibition of glioma cell proliferation and survival was found to be dependent on the mGmt status (15). notably, one clinical study found that significant and prolonged depletion of O 6 -alkylguanine-dna-alkyltransferase (aGat) activity was produced by metronomic chemotherapy of tmZ (16).…”

mentioning

confidence: 99%

Metronomic treatment of temozolomide increases anti-angiogenicity accompanied by down-regulated O6-methylguanine-DNA methyltransferase expression in endothelial cells

Ko¹,

Lee

Joe

et al. 2011

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

Abstract. metronomic chemotherapy is a continuous lowdose administration of chemotherapeutic agents to minimize toxicity and target tumor-associated endothelial cells. this therapy is beneficial to anti-angiogenic efficacy which is linked to the inhibition of tumor growth. in the present study, we compared the anti-angiogenicity of temozolomide in human umbilical vein endothelial cells (huVEcs) between conventional and metronomic treatment. metronomic treatment of temozolomide (tmZ) (6.25 and 12.5 µm) showed increased inhibition of the proliferation of huVEcs compared to an equivalent conventional treatment of tmZ. the differential effects between conventional and metronomic treatment of tmZ were also noted in cell migration and angiogenic tube formation. notably, the expression level of O 6 -methylguanine-dna methyltransferase (mGmt) was markedly reduced in the huVEcs treated with metronomic tmZ (12.5 and 25 µm) compared to cells treated with conventional treatment of tmZ. accordingly, huVEcs treated with metronomic treatment of tmZ were more sensitive to tmZ treatment. taken together, metronomic chemotherapy with tmZ enhances the inhibition of angiogenesis accompanied by the down-regulation of mGmt expression in endothelial cells when compared to conventional chemotherapy.

show abstract

“…Western blotting was conducted as described previously (15). Membranes were probed for MGMT (clone MT5.1) CD29/integrin b 1 , FAK(pY397; all from BD Biosciences), FAK (Upstate), integrin a 5 (Cell Signaling), or b-actin (Sigma-Aldrich).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…We have previously characterized a novel inverse relationship between MGMT expression and GBM angiogenicity (15). Tumor angiogenesis and invasion, the major hallmarks of GBM aggressiveness share interdependent molecular mechanisms of regulation (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

O(6)-Methylguanine-DNA Methyltransferase Is a Novel Negative Effector of Invasion in Glioblastoma Multiforme

Chahal

Abdulkarim

et al. 2012

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

The dismal prognosis of glioblastoma multiforme (GBM) is mostly due to the high propensity of GBM tumor cells to invade. We reported an inverse relationship between GBM angiogenicity and expression of the DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT), which has been extensively characterized for its role in resistance to alkylating agents used in GBM treatment. In the present study, given the major role of angiogenesis and invasion in GBM aggressiveness, we aimed to investigate the relationship between MGMT expression and GBM invasion. Stable overexpression of MGMT in the U87MG cell line significantly decreased invasion, altered expression of invasion-related genes, decreased expression of a 5 b 1 integrin and focal adhesion kinase, and reduced their spindle-shaped morphology and migration compared with the empty vector control. Conversely, short hairpin RNA-mediated stable knockdown of MGMT or its pharmacologic depletion in the MGMT-positive T98G cell line were required for increased invasion. The inverse relationship between MGMT and invasion was further validated in primary GBM patient-derived cell lines. Using paraffin-embedded tumors from patients with newly diagnosed GBM (n ¼ 59), tumor MGMT promoter hypermethylation (MGMT gene silencing) was significantly associated with increased immunohistochemical expression of the proinvasive matricellular protein secreted protein acidic and rich in cysteine (SPARC; P ¼ 0.039, x 2 test). Taken together, our findings highlight for the first time the role of MGMT as a negative effector of GBM invasion. Future studies are warranted to elucidate the role of SPARC in the molecular mechanisms underlying the inverse relationship between MGMT and GBM invasion and the potential use of MGMT and SPARC as biomarkers of GBM invasion.

show abstract

MGMT modulates glioblastoma angiogenesis and response to the tyrosine kinase inhibitor sunitinib

Cited by 77 publications

References 41 publications

MGMT Inhibition Restores ERα Functional Sensitivity to Antiestrogen Therapy

MGMT Inhibition Restores ERα Functional Sensitivity to Antiestrogen Therapy

Metronomic treatment of temozolomide increases anti-angiogenicity accompanied by down-regulated O6-methylguanine-DNA methyltransferase expression in endothelial cells

O(6)-Methylguanine-DNA Methyltransferase Is a Novel Negative Effector of Invasion in Glioblastoma Multiforme

Contact Info

Product

Resources

About