Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression

Dec 10, 2015International journal of oncology

Sulforaphane may reverse chemotherapy resistance in brain cancer cells by lowering a protective protein through a specific cell pathway

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Abstract

Sulforaphane (SFN) significantly suppressed the growth of TMZ-resistant glioblastoma cells in a mouse model.

Temozolomide (TMZ) resistance in glioblastoma is associated with high levels of MGMT expression and activated NF-κB signaling.
TMZ-resistant cell lines showed IC50 values indicating decreased sensitivity to TMZ compared to untreated cells.
SFN inhibited proliferation of TMZ-resistant glioblastoma cells and reduced MGMT expression.
Combination treatment with SFN and TMZ synergistically enhanced cell death and reduced survival capabilities in resistant cells.
In a mouse model, SFN treatment led to significant suppression of tumor growth and increased cell death in TMZ-resistant glioblastoma xenografts.

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The survival benefits of patients with glioblastoma (GBM) remain unsatisfactory due to the intrinsic or acquired resistance to temozolomide (TMZ). We elucidated the mechanisms of sulforaphane (SFN) reverse TMZ resistance in TMZ-inducing cell lines by inhibiting nuclear factor-κB (NF-κB) transcriptional activity. TMZ-resistant cell lines (U87-R and U373-R) were generated by stepwise (6 months) exposure of parental cells to TMZ. Luciferase reporter assay, biochemical assays and subcutaneous tumor establishment were used to characterize the antitumor effect of SFN. MGMT expression and 50% inhibiting concentration (IC50) values of TMZ in GBM cell lines were assessed. Next, we established that U87-R and U373-R cells presenting high IC50 of TMZ, activated NF-κB transcription and significantly increased MGMT expression compared with untreated cells. Furthermore, we revealed that SFN could significantly suppress proliferation of TMZ-resistant GBM cells. In addition, SFN effectively inhibited activity of NF-κB signaling pathway and then reduced MGMT expression to reverse the chemo-resistance to TMZ in T98G, U87-R and U373-R cell lines. Sequential combination with TMZ synergistically inhibited survival capability and increased the induction of apoptosis in TMZ-resistant GBM cells. Finally, a nude mouse model was established with U373-R cell subcutaneous tumor-bearing mice, and results showed that SFN could remarkably suppress cell growth and enhance cell death in chemo-resistant xenografts in the nude mouse model. Collectively, the present study suggests that the clinical efficacy of TMZ-based chemotherapy in TMZ-resistant GBM may be improved by combination with SFN.

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Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression

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