Novel Indole-fused benzo-oxazepines (IFBOs) inhibit invasion of hepatocellular carcinoma by targeting IL-6 mediated JAK2/STAT3 oncogenic signals.

Abstract

Inspired by the well-documented tumor protecting ability of paullones, recently, we synthesized novel paullone-like scaffolds, indole-fused benzo-oxazepines (IFBOs), and screened them against hepatocellular carcinoma (HCC) specific Hep-G2 cells. Three of the synthesized compounds significantly attenuated the progression of HCC in vitro. By computational studies, we further discovered that IFBOs exhibited a stable binding complex with the IL-6 receptor. In this context, we investigated in vivo study using the nitrosodiethyl amine (NDEA)-induced HCC model, which strengthened our previous findings by showing the blockade of the IL-6 mediated JAK2/STAT3 oncogenic signaling pathway. Treatment with IFBOs showed remarkable attenuation of cellular proliferation, as evidenced through a decrease in the number of nodules, restoration of body weight, oxidative stress parameters, liver marker enzymes and histological architecture. Interestingly, using a metabolomic approach we further discovered that IFBOs can restore the perturbed metabolic profile associated with the HCC condition to normalcy. Particularly, the efficacy of compound 6a for an anti-HCC response was significantly better than the marketed chemotherapeutic drug, 5-fluorouracil. Altogether, these remarkable findings open up possibilities of developing IFBOs as novel future candidate molecules for plausible alternatives for HCC treatment.

• Authors: Ashok K Singh, Archana S Bhadauria, Umesh Kumar, Vinit Raj, Amit Rai, Pranesh Kumar, Amit K Keshari, Dinesh Kumar, Biswanath Maity, Sneha Nath, Anand Prakash, Sudipta Saha
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 5932 (04 12 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 29651140 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Indoles
• Interleukin-6
• Oxazepines
• STAT3 Transcription Factor
• STAT3 protein, human
• JAK2 protein, human
• Janus Kinase 2

Topics

• Apoptosis (drug effects)
• Carcinogenesis (drug effects)
• Carcinoma, Hepatocellular (drug therapy, genetics, pathology)
• Cell Movement
• Cell Proliferation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Hep G2 Cells
• Humans
• Indoles (chemistry, pharmacology)
• Interleukin-6 (genetics)
• Janus Kinase 2 (genetics)
• Liver Neoplasms (drug therapy, genetics, pathology)
• Oxazepines (chemistry, pharmacology)
• STAT3 Transcription Factor (genetics)
• Signal Transduction (drug effects)