Abstract
Glioblastoma (GB), a grade IV glioma, with high heterogeneity and chemoresistance, obligates a multidimensional antagonist to debilitate its competence. Considering the previous reports on thioesters as antitumor compounds, this paper investigates on use of this densely functionalized sulphur rich molecule as a potent anti-GB agent. Bio-evaluation of 12 novel compounds, containing α-thioether ketone and orthothioester functionalities, identified that five analogs exhibited better cytotoxic profile compared to standard drug cisplatin. Detailed toxicity studies of top compound were evaluated in two cell lines, using cell viability test, apoptotic activity, oxidative stress and caspase activation and RNA-sequencing analysis, to obtain a comprehensive molecular profile of drug activity. The most effective molecule presented half maximal inhibitory concentration (IC50) values of 27 μM and 23 μM against U87 and LN229 GB cells, respectively. Same compound effectively weakened various angiogenic pathways, mainly MAPK and JAK-STAT pathways, downregulating VEGF. Transcriptome analysis identified significant promotion of apoptotic genes, and genes involved in cell cycle arrest, with concurrent inhibition of various tyrosine kinase cascades and stress response genes. Docking and immunoblotting studies suggest EGFR as a strong target of the orthothioester identified. Therefore, orthothioesters can potentially serve as a multi-dimensional chemotherapeutic possessing strong cytotoxic, anti-angiogenic and chemo-sensitization activity, challenging glioblastoma pathogenesis.
Highlights
IntroductionThe high heterogeneity exhibited within GB tumors render it
Glioblastoma (GB) is a type of brain tumor with almost 100% recurrence rate and high resistance to current treatment modalities
The high heterogeneity exhibited within GB tumors render it unresponsive agents andand demands a significant clinical need unresponsive to tosingle-target single-targetcytotoxic/anti-angiogenic cytotoxic/anti-angiogenic agents demands a significant clinical for new multi-dimensional oncogenic inhibitors for need for new multi-dimensional oncogenic inhibitors for GB
Summary
The high heterogeneity exhibited within GB tumors render it. Glioblastoma (GB) is a type of brain tumor with almost 100% recurrence rate and high resistance to current treatment modalities. The high heterogeneity exhibited within GB tumors render it unresponsive agents andand demands a significant clinical need unresponsive to tosingle-target single-targetcytotoxic/anti-angiogenic cytotoxic/anti-angiogenic agents demands a significant clinical for new multi-dimensional oncogenic inhibitors for GB. Need for new multi-dimensional oncogenic inhibitors for GB. Angiogenesis feature of GB, to the overexpression of vascularof endothelial. GB, attributed to the overexpression vascular growth factor (VEGF). Few of the most significant proangiogenic regulators that stimulate angiogenesis endothelial growth factor (VEGF). Few of the most significant proangiogenic regulators that stimulate indirectly by inducing mRNA VEGF expression include the growth factors epidermal growth factor angiogenesis indirectlyVEGF by inducing mRNA expression include the growth factors epidermal (EGF), factor
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