Senescence Induced by DNA Demethylating Drugs to Treat Solid Tumors
DNA methylation is a process by which methyl groups are added to DNA, modifying its function. When located in a gene promoter, DNA methylation typically acts to repress gene transcription. DNA methylation is aberrant in all forms of cancer, but it is not fully understood how this occurs and what is its role in tumorigenesis. Aberrant DNA methylation in cancer can be generated following cell transformation or generated in a programmed manner in a subpopulation of tissue cells during normal aging and cell senescence predisposing them for tumorigenesis. Regardless, DNA methylation contributes to the tumor state by inhibiting the plasticity of cell differentiation DNA methylation. DNA demethylating agents, such as decitabine, exert their anticancer activity by triggering a drug-induced cell senescence program that induces cancer cells to exit cell cycle and stop proliferating, which is considered per se an important tumor suppressive mechanism. Moreover, specific senescence-associated DNA methylation changes are observed in normal and cancer cells. In this chapter we will describe advances in our knowledge about (i) the development of novel generation DNA demethylating drugs and (ii) the molecular mediators, prognostic indicators, and tailoring tools for DNA demethylating drug-induced senescence in cancer cells. We focus on solid tumors, in particular on gastrointestinal tumors, and we describe the current evidence that epigenetic hypomethylation therapies possess significant immunomodulatory effects by controlling cell senescence. The immunomodulatory activities of DNA demethylating drugs might lead to improved immune recognition of cancer/senescent cells and on novel immunotherapies through combinatorial epigenetic immunotherapy approaches.
KeywordsEpigenetic Therapy Guadecitabine DNA hypomethylating agents Hepatocellular Carcinoma Anti-cancer Therapies Solid Tumors
This work was supported by grants from the European Social Fund and European Regional Development Fund – Project MAGNET (No. CZ.02.1.01/0.0/0.0/15_003/0000492).
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