title: Artesunate obliterates experimental hepatocellular carcinoma in rats through suppression of IL-6-JAK-STAT signalling.
abstract: Activation of the IL-6 mediated JAK-STAT (Janus associated kinase-signal transducer and activator of transcription) oncogenic signalling plays a major role in hepatocellular carcinoma pathogenesis. The aim of this study is to assess the anti-tumour, anti-proliferative and apoptotic potential of artesunate and its capacity to modulate JAK-STAT pathway in a nitrosodiethylamine mediated experimental hepatocellular carcinoma model. Administration of nitrosodiethylamine (200mg/kg body weight by i.p. Injections) to rats resulted in alterations of liver pathophysiological parameters such as increased relative liver weight, and increased tumour nodule occurrence. It also increased the levels of serum marker enzymes (AST, ALT, ALP, LDH, and γGT) and tumour biomarker (AFP) levels suggestive of its capacity to cause liver tumourigenesis. Additionally, the immunohistochemistry of liver sections pertaining to nitrosodiethylamine administered animals showed increased detection of AgNOR, PCNA, and GST-Pi positive cells suggestive of its capacity to promote liver proliferation associated tumourigenesis. On the contrary, artesunate (25mg/kg bodyweight) supplementation to nitrosodiethylamine administered animals decreased all the above mentioned pathophysiological, biochemical, and immunohistochemistry parameters suggesting its anti-tumour and anti-proliferative potential. Furthermore, immunoblot analysis showed significant up-regulation of IL-6, GP130, JAK-2, STAT-3 (pY705), Bcl-xL, Bcl-2 and simultaneous down-regulation of Caspase-3, PARP and SOCS-3 in nitrosodiethylamine administered animals. Nevertheless, the immunoblot analysis revealed vice-versa on artesunate supplementation to nitrosodiethylamine administered animals, indicating promotion of the feedback loop inhibition mechanism through SOCS3 up-regulation thereby leading to suppression of JAK-STAT signalling. Overall all these findings substantiate that artesunate promotes anti-tumour, anti-proliferation and apoptosis against nitrosodiethylamine mediated hepatocellular carcinoma.
authors.affiliation: Cardiomyocyte toxicity and oncology research lab, Department of Bioinformatics, School of Chemical and Biotechnology, SASTRA University, Thirumalaisamudram, Thanjavur-613402, Tamilnadu, India.
authors.forename: M
authors.initials: M
authors.lastname: Ilamathi
authors.affiliation: Central animal facility, SASTRA University, Thirumalaisamudram, Thanjavur-613402, Tamilnadu, India.
authors.forename: P C
authors.initials: PC
authors.lastname: Prabu
authors.affiliation: Lifestyle diseases biology lab, Department of Biotechnology, School of Chemical and Biotechnology, SASTRA University, Thirumalaisamudram, Thanjavur-613402, Tamilnadu, India. Electronic address: ashokayyappa@scbt.sastra.edu.
authors.forename: K Ashok
authors.initials: KA
authors.lastname: Ayyappa
authors.affiliation: Cardiomyocyte toxicity and oncology research lab, Department of Bioinformatics, School of Chemical and Biotechnology, SASTRA University, Thirumalaisamudram, Thanjavur-613402, Tamilnadu, India. Electronic address: sivaramakrishnan@scbt.sastra.edu.
authors.forename: V
authors.initials: V
authors.lastname: Sivaramakrishnan
mesh_terms: D000818:Animals; D037621:Artemisinins / Q000494:pharmacology / Q000627:therapeutic use*; D000077332:Artesunate; D014408:Biomarkers, Tumor / Q000097:blood; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D053938:DNA Fragmentation / Q000187:drug effects; D015151:Immunoblotting; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016622:Silver Staining; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: D037621:Artemisinins; D014408:Biomarkers, Tumor; D015850:Interleukin-6; D018809:Proliferating Cell Nuclear Antigen; D050796:STAT3 Transcription Factor; D000509:alpha-Fetoproteins; D000077332:Artesunate; D053612:Janus Kinases
keywords: AgNOR; Anti-cancer agent; Artesunate; Hepatocellular carcinoma; Histopathology