The tumor operates on an energy deficit due to high rates of ATP turnover [36] especially under hypoxia to maintain survival. The cellular adaptations to

chemotherapy including increased repair of DNA damage, enhanced drug inactivation [37], elevated intracellular levels of glutathione, overexpression of multiple drug resistance (MDR) [38], and other membrane efflux pumps that mediate resistance represent an additional drain on tumor ATP economy, resulting in a mismatch between ATP supply and ATP demand. Resensitization demands a shift in perspective and treatment ethos: In the current paradigm of metastatic cancer, time is a one-way arrow pointing inevitably toward therapeutic failure, which may justify aggressive chemotherapy protocols, CDK phosphorylation often at the expense of quality of life considerations, to extend life. Clearly then, resensitization KU-60019 in vitro has important diagnostic and therapeutic implications and needs to be examined on a more systematic, rather than on an anecdotally “one off” or case-by-case, basis. Epigenetics stands at the intersection of nature versus nurture whereby epigenetic marks dynamically—and often reversibly—change or readjust in response

to environmental factors. Cancer cells, challenged by an ever-changing environment, and in a constant state of flux, epigenetically “tinker” with genes, activating or inactivating them, in response to a variable environment. While the specific molecular mechanisms involved in resensitization or, perhaps more appropriately, “episensitization,” which constitutes a reboot or restore to the original state, are admittedly unclear, Ribonucleotide reductase multiplicity may be more important than specificity, i.e., the simultaneous inhibition of multiple pharmacologic targets that are crucial to cellular metabolism and energy status. Unlike targeted or molecular therapies, which aim to strictly regulate one pathway, one target, or one gene, epigenetic agents are

“Swiss Army Knives” in the anticancer armamentarium, modifying the chromatin structure and thus influencing expression of multiple genes and a panoply of pathways including ribosomal proteins, oxidative phosphorylation, DNA/RNA polymerases, and Wnt/β-catenin signaling among others through inhibition of HDACs and DNA MTases [39]. Epigenetic modulators, like decitabine and the other epigenetic agents listed in Table 1, replace the specificity of molecularly targeted agents, designed to inhibit specific kinases, with the multiplicity of gene reactivation. As a therapeutic strategy, epigenetic modulation may seem, at present, like a relative shot in the dark, given the nonspecific nature of its gene-activating effects. However, since cancer cells build and require a growth-conducive microenvironment, which depends on silencing target genes, reactivation of these genes that, in aggregate, encompass a broad range of biologic functions may destabilize the tumor.