Inhibition of STAT3 reverses drug resistance acquired in temozolomide-resistant human glioma cells.

The alkylating agent temozolomide (TMZ) is an effective drug used for the treatment of malignant gliomas. However, tumor relapse combined with the development of drug resistance remains a significant problem. To clarify the mechanism of the resistance of glioma cells to TMZ chemotherapy, TMZ-resistant glioma cell lines (TR cells) were generated using U373 and U251 human glioma cells, and TMZ-resistance was confirmed via viability and apoptosis assays. The TMZ-resistance of TR cells was not associated with the TMZ-resistance molecule O(6)-methylguanine-DNA-methyltransferase. Notably, the expression level of signal transducers and activators of transcription 3 (STAT3) and serine 727-phosphorylated STAT3 (pSTAT3-Ser727) was highly increased in TR cells, while that of 705-phosphorylated STAT3 (pSTAT3-Tyr705) was decreased. The inhibition of STAT3 expression by small interfering RNA enhanced TR cell TMZ sensitivity. These results suggest that STAT3 contributes to TMZ-resistance in gliomas and is a potential target for the reversal of TMZ-resistance in patients with a recurrent glioma.

Metronomic treatment of temozolomide increases anti-angiogenicity accompanied by down-regulated O(6)-methylguanine-DNA methyltransferase expression in endothelial cells.

Metronomic chemotherapy is a continuous low-dose 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.