STAT3 inhibition overcomes temozolomide resistance in glioblastoma by downregulating MGMT expression.

Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with a poor prognosis. Current standard treatment includes chemotherapy with the DNA-alkylating agent temozolomide concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to temozolomide-induced DNA damage due to elevated expression of the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT). Here, we show that upregulation of both MGMT and STAT3 was accompanied with acquisition of temozolomide resistance in the GBM cell line U87. Inactivation of STAT3 by inhibitor or short hairpin RNA (shRNA) downregulated MGMT expression in GBM cell lines. MGMT upregulation was not observed by the treatment of interleukin (IL)-6 which is a strong activator of STAT3. Contrarily, forced expressed MGMT could be downregulated by STAT3 inhibitor which was partially rescued by the proteasome inhibitor, MG132, suggesting the STAT3-mediated posttranscriptional regulation of the protein levels of MGMT. Immunohistochemical analysis of 44 malignant glioma specimens showed significant positive correlation between expression levels of MGMT and phosphorylated STAT3 (p-STAT3; P < 0.001, r = 0.58). Importantly, the levels of both MGMT and p-STAT3 were increased in the recurrence compared with the primary lesion in paired identical tumors of 12 cases. Finally, we showed that STAT3 inhibitor or STAT3 knockdown potentiated temozolomide efficacy in temozolomide-resistant GBM cell lines. Therefore, STAT3 inhibitor might be one of the candidate reagents for combination therapy with temozolomide for patients with temozolomide-resistant GBM.

Kohsaka S ，Wang L ，Yachi K ，Mahabir R ，Narita T ，Itoh T ，Tanino M ，Kimura T ，Nishihara H ，Tanaka S ... -  《-》

Silencing SATB1 overcomes temozolomide resistance by downregulating MGMT expression and upregulating SLC22A18 expression in human glioblastoma cells.

Yang B ，Ma YB ，Chu SH 《-》

Inhibition of histone deacetylation potentiates the evolution of acquired temozolomide resistance linked to MGMT upregulation in glioblastoma xenografts.

Kitange GJ ，Mladek AC ，Carlson BL ，Schroeder MA ，Pokorny JL ，Cen L ，Decker PA ，Wu W ，Lomberk GA ，Gupta SK ，Urrutia RA ，Sarkaria JN ... -  《-》

Inhibition of GSH synthesis potentiates temozolomide-induced bystander effect in glioblastoma.

Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with poor prognosis. Current standard treatment includes chemotherapy using DNA alkylating agent temozolomide (TMZ) concomitant with surgical resection and/or irradiation. However, GBM patients exhibit various levels of the elevated expression of DNA repair enzyme, due to MGMT causing resistance to TMZ. Determination of the MGMT-positive population of primary tumor is important to evaluate the therapeutic efficacy of TMZ. Here we generated TMZ-resistant GBM cells by introducing MGMT into TMZ-sensitive GBM cell line KMG4, and established a model to assess the TMZ-induced bystander effect on TMZ-resistant cells. By mixing TMZ-resistant and -sensitive cells, GBM tumors with MGMT positivity as 50%, 10%, and 1% were generated in vivo. We could not observe any bystander effect of TMZ-induced cell death in tumor with 50% MGMT positivity. Although the bystander effect was observed within 20 days in the case of tumor with 1% MGMT positivity, final tumor size at day 28 was the same as control without sensitive cells. This bystander effect was observed in vitro using conditioned medium of TMZ-damaged GBM cells, and PCR array analysis indicated that the conditioned medium stimulated stress and toxicity pathway and upregulated anti-oxidants genes expression such as catalase and SOD2 in TMZ-resistant cells. In addition, the reduction of the activity of anti-stress mechanism by using inhibitor of GSH synthesis potentiated TMZ-induced bystander effect. These results suggest that GSH inhibitor might be one of the candidates for combination therapy with TMZ for TMZ-resistant GBM patients.

Kohsaka S ，Takahashi K ，Wang L ，Tanino M ，Kimura T ，Nishihara H ，Tanaka S ... -  《-》

Alkylpurine-DNA-N-glycosylase confers resistance to temozolomide in xenograft models of glioblastoma multiforme and is associated with poor survival in patients.

Agnihotri S ，Gajadhar AS ，Ternamian C ，Gorlia T ，Diefes KL ，Mischel PS ，Kelly J ，McGown G ，Thorncroft M ，Carlson BL ，Sarkaria JN ，Margison GP ，Aldape K ，Hawkins C ，Hegi M ，Guha A ... -  《-》