p53 Inhibitors as Cancer Sensitizing Agents

摘要: The formation and the development of neoplasia is a Darwinian selection for cells that progressively lose negative regulators simultaneously reinforce positive modulators growth. For example, regulatory mechanisms involved in checkpoint control apoptosis are needed to guarantee genetic stability healthy cells, but detrimental cancer cells. possibility pharmacologically tune such systems therapy represents big challenge selectively destroy protect thus favoring regeneration tissue recovery. One well-known key player p53. p53 activated following different stresses, including altered signals from environment, DNA damage by chemical physical agents (genotoxic stress), assembly/disassembly microtubules, oncogene activation hypoxia [1-3]. All these cellular stresses result cell-cycle arrest, and/or repair, depending on cell type, their developmental time point, character entity insult (Fig. 12.1) [4, 5]. However, proper stress-response also orchestrated through choice its partners transcriptional readout [6–8]. Following insults, there three major decision points. first one occurs after directs toward or repair. second repair establishes whether not was successful can resume proliferation. third happens when unsuccessful. In this case must choose between irreversible growth arrest mitotic catastrophe. all points, actor, which function ensures determined amount duration activation. Indeed, strong sustained correlates with higher chances versus [9]. success requirement genotoxic both largely depend proliferation rate unrepaired chromosomal breaks be lethal dividing tolerated quiescent will never detect being postmitotic. best examples radiosensitivity brain, most radioresistant organs adult, sensitive embryos [10]. Thus, has an important “social” function: ensuring elimination irreversibly damaged and, consequently, dangerous inducing them die benefit organism. functions unambiguously state role as tumor suppressor gene. Mutation gene found more than 50% human Chapter 12 Inhibitors Cancer Sensitizing Agents