SNAP reverses temozolomide resistance in human glioblastoma multiforme cells through down‐regulation of MGMT

Nov 15, 2019FASEB journal : official publication of the Federation of American Societies for Experimental Biology

SNAP may reverse drug resistance in human glioblastoma cells by lowering MGMT levels

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Abstract

Nitric oxide donor nitroso-acetylpenicillamine (SNAP) may reverse temozolomide resistance in glioblastoma multiforme cells.

SNAP demonstrated antitumor effects on both temozolomide-sensitive and temozolomide-resistant glioma cells.
It induced cell death, disrupted mitochondrial function, and activated hypoxia-inducing factor 1.
SNAP resensitized temozolomide-resistant glioblastoma cells to temozolomide by down-regulating MGMT expression.
The mechanism involved post-translational modifications of specific proteins that affect MGMT stability.
Combined treatment of SNAP and temozolomide enhanced tumor growth inhibition.

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Glioblastoma multiforme (GBM) is the most frequently occurring and gravest primary tumor of the CNS in adults. The development of chemoresistance to temozolomide (TMZ), the first-line chemotherapy for GBM, is an important factor contributing to poor treatment outcomes. Down-regulation of-6-methylguanine-DNA methyltransferase (MGMT) expression in GBM cells is an attractive strategy for overcoming TMZ resistance and improving outcomes. This study revealed that the nitric oxide (NO) donor-nitroso--acetylpenicillamine (SNAP) exerts antitumorigenic effects on TMZ-sensitive and TMZ-resistant (TMZ-R) glioma cells. Pretreatment with SNAP not only induced apoptosis, mitochondrial dysfunction, and hypoxia-inducing factor 1, but also resensitized TMZ-R GBM cells to TMZ through down-regulation of MGMT expression. SNAP acted principally through post-translational modification of p53, phosphorylated N-myc downstream regulated gene 1, and MGMT protein stability in TMZ-R GBM cells. Additionally, when applied together, SNAP and TMZ enhanced the inhibition of tumor growthand. This study sheds new light on a potential strategy to overcome TMZ resistance in GBM and thus possesses the potential for prolonging survival of patients with GBM.-Tsai, C.-K., Huang, L.-C., Wu, Y.-P., Kan, I.-Y., Hueng, D.-Y. SNAP reverses temozolomide resistance in human glioblastoma multiforme cells through down-regulation of MGMT. O S N in vitro in vivo

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SNAP reverses temozolomide resistance in human glioblastoma multiforme cells through down‐regulation of MGMT

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