N-end rule pathway inhibition assists colon tumor regression via necroptosis.

摘要: Recent study has shown that N-end rule pathway, an ubiquitin dependent proteolytic system, counteracts cell death by degrading many antisurvival protein fragments like BCLxL, BRCA1, RIPK1, etc. Inhibition of the pathway can lead to metabolic stabilization proapoptotic thereby sensitizing cells programmed death. Receptor interacting serine-threonine kinase-1 (RIPK1) is one upstream regulators necrosis known as necroptosis. Necroptosis particularly gaining attention cancer biologists it provides alternate therapeutic modality kill cells, which often evolve multiple strategies circumvent growth inhibition apoptosis. Utilizing over expression biotin receptor in herein, we report coadministration synthetic hetero-bivalent inhibitor RFC11 and anticancer drug shikonin solubilized a stable receptor-targeted liposome exhibited significant synergistic antitumor effect both subcutaneous orthotopic mouse colon tumor model through induction necroptosis with distinctive upregulation RIPK1. Besides developing newly targeted formulation for induction, this first vivo evidence demonstrating potent enhance efficacy conventional chemotherapeutics.