Plant-derived natural compounds aiding SOCS1 mediated JAK1 inhibition, a novel mechanism of combinatorial cancer chemotherapy

摘要

Abstract Numerous drugs have been used in the past to treat HNSC cancer through tumor suppression and immune modulation mechanisms. However, none of them achieved complete tumor remission. Synthetic drugs targeting tumor cells have side effects, and the tumor often acquires resistance against them. A subfamily of tyrosine kinases called Janus Kinases (JAKs) is observed to be over-expressed in various solid tumors, including HNSC. JAKs directly activate a family of transcription factors, Signal Transducers and Activators of Transcription (STATs) and induce a signaling cascade collectively known as JAK/STAT pathways. STATs are responsible for the regulated production of many inflammatory cytokines and growth factors that are beneficial to the tumor cells, favouring them to sustain themselves in a hostile microenvironment. Hence, inhibitors of JAK have been explored previously and SOCS 1 has been shown to be a known direct and most potent inhibitor of JAK1 among the family of SOCSs proteins. The study presented here proposes a mechanism to inhibit the JAK/STAT pathway by inhibiting the JAK1 protein using small molecules of plant origin. The study thereby proposes three inhibitors viz., withaferin A, silymarin, and hypericin, to have significant potential to inhibit JAK1 protein, known to be upregulated in tumors. SOCS1 was also identified to be upregulated in an HNSC tumor samples and is known to inhibit JAK-STAT pathway. Our 3 potent inhibitors, withaferin A, silymarin, and hypericin had the ability to also bind to the SOCS1-JAK1complex thus stabilizing it thus further potentiating the inhibition of JAK-STAT pathway. The three inhibitors explored in the present study can prevent JAK phosphorylation and activation in preventive and therapeutic application. The study proposes a therapy that can be employed in combination with other cancer therapies, thus increasing the overall efficiency of the treatment.