title: Revisiting p53 for cancer-specific chemo- and radiotherapy: ten years after.
abstract: Despite intense studies, highly effective therapeutic strategies against cancer have not yet been fully exploited, because few true cancer-specific targets have been identified. Most modalities, perhaps with the exception of radiation therapy, target proliferating cells, which are also abundant in normal tissues. Thus, most current cancer treatments have significant side effects. More than 10 years ago, the tumor suppressor p53 was first explored as a cancer-specific target. At the time, the approach was to introduce a normal p53 gene into mutant p53 (mp53) tumor cells to induce cell cycle arrest and apoptosis. However, this strategy did not hold up and mostly failed in subsequent clinical studies. Recent research developments have now returned p53 to the limelight. Several studies have reported that mutant or null p53 tumor cells undergo apoptosis more easily than genetically matched, normal p53 counterparts when inhibiting a specific stress kinase in combination with standard chemotherapy or when exposed to an ataxia-telangiectasia mutated (ATM) kinase inhibitor and radiation, thus achieving true cancer specificity in animal tumor models. This short review highlights several of these recent studies, discusses possible mechanism(s) for mp53-mediated "synthetic lethality," and the implications for cancer therapy.
authors: Department of Radiation Oncology; Virginia Commonwealth University; Richmond, VA USA; Department of Biochemistry and Molecular Biology; Virginia Commonwealth University; Richmond, VA USA.
authors: Jason M
authors: JM
authors: Beckta
authors: Department of Radiation Oncology; Virginia Commonwealth University; Richmond, VA USA; Department of Biochemistry and Molecular Biology; Virginia Commonwealth University; Richmond, VA USA.
authors: Syed Farhan
authors: SF
authors: Ahmad
authors: Department of Biomedical Engineering; Virginia Commonwealth University; Richmond, VA USA; Massey Cancer Center; Virginia Commonwealth University; Richmond, VA USA.
authors: Hu
authors: H
authors: Yang
authors: Department of Radiation Oncology; Virginia Commonwealth University; Richmond, VA USA; Department of Biochemistry and Molecular Biology; Virginia Commonwealth University; Richmond, VA USA; Massey Cancer Center; Virginia Commonwealth University; Richmond, VA USA.
authors: Kristoffer
authors: K
authors: Valerie
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D015316:Genetic Therapy; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM; DNA damage response; DNA repair; MAPKAP kinase 2; p38