Sphingosine kinase inhibitor regulates pro‐inflammatory cytokines to subdue the neoplastic lesions in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC), is the most leading cause of cancer‐related death in all over the world (seems to more than 80% of death cases). It is frequently linked with continuous hepatocytes death, inflammatory cell infiltration, and compensatory liver regeneration with higher angiogenic rate. Considering the different signalling process during this tumorogenesis with the involvement of new ‘lead’ identification of different sources, desire to be less toxic and higher bioavailability. The use of live, attenuated or genetically compensated microbes or its cellular component(s) or metabolites has begun to emerge as a potential new approach in medicinal research to deliver bioactive entities. Thus, advancing our knowledge of such microbes‐mediated therapy may suggest new avenues for therapeutic intervention in many fatal diseases.Sphingosine kinase inhibitor (SKI) II has been reported as a dual inhibitor of sphingosine kinases (SKs) 1 and 2 and has been extensively used to prove the involvement of SKs and sphingosine‐1‐phosphate (S1P) in cellular processes and able to induce apoptosis in human HepG2 (Hepatocellular carcinoma cell, human) cells, as characterized by phosphatidylserine serine exposure, activation of series of caspases and cleaved PARP. SKI also modulates the various transcription factors like NF‐kB‐65, p53 through regulation of cell proliferation exerted the death cause. Moreover, this study also focused that SKI effectively suppressed diethylnitrosamine (DEN) induced liver inflammation and hyperplasia in murine, also regulated the lipid peroxidation and enzymic antioxidants (SOD, CAT, GPx, GR and GST) status with an improvement of their survival rate. It reduced the elevated level of cytokines including tumor necrosis factors, interleukins, interferon (alpha and gamma), and transforming growth factors in hepatocytes from liver fibrosis bearing mice. As evident from an immunochemical analysis, DEN‐induced neoplastic lesions may up‐regulate the various growth factors including EGF, HGF, endothelin‐1 regulation with promoting angiogenic activity via modulation of CD34, VEGF, HIF‐1α expression and we found that the alteration of these changes were balanced by SKI treatment in vivo system. So taken together, these finding indicated that, SKI may recover in hyperproliferating cancer cells with tumor growth regulation in carcinogen‐exposed rodent system. In future direction, we will check the p53−/− and cmyc−/− mice that hoe it could regulate cancer metastasis with this SKI. and the involvement of od tumor microenvironment.Support or Funding InformationCSIR and Department of Science and Technology, IndiaThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.