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Immune evasion in cancer: Mechanistic basis and therapeutic strategies
Vinay, D.S.,Ryan, E.P.,Pawelec, G.,Talib, W.H.,Stagg, J.,Elkord, E.,Lichtor, T.,Decker, W.K.,Whelan, R.L.,Kumara, H.M.C.S.,Signori, E.,Honoki, K.,Georgakilas, A.G.,Amin, A.,Helferich, W.G.,Boosani, C. Saunders Scientific Publications ; Academic Press 2015 SEMINARS IN CANCER BIOLOGY Vol.35 No.suppl
Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through ''equilibrium'' and ''senescence'' before re-emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown to possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, dysregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection.
Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy
Putt, Karson S,Chen, Grace W,Pearson, Jennifer M,Sandhorst, Joseph S,Hoagland, Martin S,Kwon, Jung-Taek,Hwang, Soon-Kyung,Jin, Hua,Churchwell, Mona I,Cho, Myung-Haing,Doerge, Daniel R,Helferich, Willi NATURE PUBLISHING GROUP 2006 NATURE CHEMICAL BIOLOGY Vol.2 No.10
Mutation and aberrant expression of apoptotic proteins are hallmarks of cancer. These changes prevent proapoptotic signals from being transmitted to executioner caspases, thereby averting apoptotic death and allowing cellular proliferation. Caspase-3 is the key executioner caspase, and it exists as an inactive zymogen that is activated by upstream signals. Notably, concentrations of procaspase-3 in certain cancerous cells are significantly higher than those in noncancerous controls. Here we report the identification of a small molecule (PAC-1) that directly activates procaspase-3 to caspase-3 in vitro and induces apoptosis in cancerous cells isolated from primary colon tumors in a manner directly proportional to the concentration of procaspase-3 inside these cells. We found that PAC-1 retarded the growth of tumors in three different mouse models of cancer, including two models in which PAC-1 was administered orally. PAC-1 is the first small molecule known to directly activate procaspase-3 to caspase-3, a transformation that allows induction of apoptosis even in cells that have defective apoptotic machinery. The direct activation of executioner caspases is an anticancer strategy that may prove beneficial in treating the many cancers in which procaspase-3 concentrations are elevated.