Battling Glioblastoma: A Novel Tyrosine Kinase Inhibitor with Multi-Dimensional Anti-Tumor Effect (Running Title: Cancer Cells Death Signalling Activation).
Anisha ViswanathanAliyu MusaAkshaya MurugesanJoão Rafael ValeCarlos A M AfonsoSaravanan Konda ManiOlli Yli-HarjaNuno R CandeiasMeenakshisundaram KandhaveluPublished in: Cells (2019)
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.
Keyphrases
- cell cycle arrest
- cell death
- tyrosine kinase
- oxidative stress
- induced apoptosis
- epidermal growth factor receptor
- pi k akt
- single cell
- signaling pathway
- genome wide
- adverse drug
- anti inflammatory
- dna damage
- endothelial cells
- molecular docking
- molecular dynamics
- case control
- molecular dynamics simulations
- squamous cell carcinoma
- heart rate
- cancer therapy
- radiation therapy
- emergency department
- quantum dots
- endoplasmic reticulum stress
- high intensity
- combination therapy