AS602801 sensitizes glioma cells to temozolomide and vincristine by blocking gap junction communication between glioma cells and astrocytes.

ABSTRACT

Previous studies showed that the chemotherapeutic effect of temozolomide (TMZ) and vincristine (VCR) against glioma might be blunted by the co-culture with astrocytes, and connexin-43 (CX43) was thought to play a vital role in the communication between glioma cells and astrocytes. In this study, we aimed to investigate the combined chemotherapeutic effect of AS602801 and TMZ/ VCR in glioma cells both. Dye transfer assay was used to evaluate the gap junction activity between U251 cells and astrocytes. Western blot and immunohistochemistry were carried out to analyse the expression of p-JNK, CX43 and CASP-3 proteins treated under different conditions. AS602801 significantly suppressed the gap junction activity between U251 cells and astrocytes. The expression of p-JNK and CX43 was remarkably inhibited by AS602801. TMZ/VCR-induced apoptosis of glioma cells was effectively enhanced by AS602801 treatment. Accordingly, the inhibitory role of TMZ/VCR in the expression of p-JNK, CX43 and CASP-3 in glioma cells was notably restored by AS602801. Furthermore, in a glioma cell xenograft, AS602801 showed an apparent capability to enhance TMZ/VCR-induced tumour cell apoptosis through altering the expression of p-JNK, CX43 and CASP-3. The findings of this study demonstrated that the co-culture of glioma cells with astrocytes blunted the tumour killing effect of TMZ and VCR. AS602801 down-regulated CX43 expression by inhibiting JNK. And AS602801 also sensitized glioma cells to TMZ/VCR by blocking the gap junction communication between glioma cells and astrocytes via down-regulating CX43, indicating its potential role as a novel adjuvant chemotherapeutic agent in the treatment of glioma.