Inhibitor of Nicotinamide Phosphoribosyltransferase Sensitizes Glioblastoma Cells to Temozolomide via Activating ROS/JNK Signaling Pathway

Abstract

Overcoming temozolomide (TMZ) resistance is a great challenge in glioblastoma (GBM) treatment. Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide and has a crucial role in cancer cell metabolism. In this study, we investigated whether FK866 and CHS828, two specific NAMPT inhibitors, could sensitize GBM cells to TMZ. Low doses of FK866 and CHS828 (5 nM and 10 nM, resp.) alone did not significantly decrease cell viability in U251-MG and T98 GBM cells. However, they significantly increased the antitumor action of TMZ in these cells. In U251-MG cells, administration of NAMPT inhibitors increased the TMZ (100 μM)-induced apoptosis and LDH release from GBM cells. NAMPT inhibitors remarkably enhanced the activities of caspase-1, caspase-3, and caspase-9. Moreover, NAMPT inhibitors increased reactive oxygen species (ROS) production and superoxide anion level but reduced the SOD activity and total antioxidative capacity in GBM cells. Treatment of NAMPT inhibitors increased phosphorylation of c-Jun and JNK. Administration of JNK inhibitor SP600125 or ROS scavenger tocopherol with TMZ and NAMPT inhibitors substantially attenuated the sensitization of NAMPT inhibitor on TMZ antitumor action. Our data indicate a potential value of NAMPT inhibitors in combined use with TMZ for GBM treatment.

Visfatin mediates doxorubicin resistance in human non–small‐cell lung cancer via Akt‐mediated up‐regulation of ABCC1

“…Although numerous studies indicated that visfatin can trigger the progression of cancers including NSCLC, 10 Targeted inhibition of visfatin can sensitize glioblastoma cells to temozolomide treatment. 12 Laboratory studies also indicated that visfatin can trigger the in vitro migration and invasion of NSCLC cancers via up-regulation of MMP-2 and MMP-9. 7 Considering that migration and invasion also contribute to drug resistance, 18 our present study, together with the published data, confirmed that visfatin might be a therapy target for NSCLC to suppress its progression.…”

“…were cultured in bronchial epithelial cell basal medium (BEBM, LONZA, Wokingham, UK) supplemented with 0.1% (v/v) human recombinant epidermal growth factor and 0.1% (v/v) insulin. Cells at passage [10][11][12][13][14][15][16][17][18][19][20] were used in this study. The Dox-resistant A549/Dox and H1793/ Dox cells were selected from A549 and H1793 cells, respectively, over 6 months by selecting cells stepwise increasing concentrations of Dox (0.01-1 μmol/L).…”

“…One recent study revealed that inhibition of visfatin can sensitize glioblastoma cells to temozolomide via activation of ROS/JNK signals. 12 Considering that visfatin can significantly promote the development of NSCLC, we, therefore, hypothesized that visfatin might also be involved in the Dox resistance of NSCLC cells.…”

Wingless promotes JNK/MMPs positive feedback loop mediate tumour microtubes expansion, glioma progression and neurodegeneration

“…JNK is upregulated in a number of tumours including GB and it has been related to glioma malignancy [29][30][31][32]. Moreover, JNK is a target for specific drugs in combination with temozolomide treatments as it was proven to play a central role in GB progression [20,[33][34][35]. However, little is known about the molecular mechanisms underlying JNK activation in glioma cells and the functional consequences for GB progression.…”

Cell to cell communication is an early event in glioblastoma

“…Glioblastoma multiforme (GB) is the most frequent and aggressive primary malignant brain tumour with a 3 per 100.000 incidence per year (Gallego, 2015). GB patients´ median survival is 12-15 months, with less than 5% of survival after 5 years (Gallego, 2015;Louis et al, 2016;McGuire, 2016;Rogers et al, 2018). The causes of GB are under debate (McGuire, 2016), 5% of the patients develop GB after a low grade astrocytoma (Alifieris and Trafalis, 2015) and the most frequent mutations include gain of function of the epidermal growth factor receptor (EGFR) (97%) and the phosphatidylinositol-3 kinase (PI3K)/phosphatase and tensin homologue (PTEN) pathways (88%) (Hayden, 2010).…”