10. Xue W, Zender L, Miething C, Dickins RA, Hernando E, et al. (2007) Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445: 656–60. 11. Sohn TA, Bansal R, Su GH, Murphy KM, Kern SE (2002) High-throughput measurement of the Tp53 response to anticancer drugs and random compounds using a stably integrated Tp53-responsive luciferase reporter. Carcinogenesis 23: 949–57. 12. Bykov VJ, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, et al. (2002) Restoration of the tumor suppressor function to mutant p53 by a low-molecular- weight compound. Nat Med 8: 282–8. 13. Vassilev LT, Vu BT, Graves BT, Carvajal D, Podlaski F, et al. (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303: 844–8. 14. Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef LG, et al. (2004) Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med 10: 1321–8. 15. Gurova KV, Hill JE, Guo C, Prokvolit A, Burdelya LG, et al. (2005) Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-kappaB- dependent mechanism of p53 suppression in tumors. Proc Natl Acad Sci USA 102: 17448–53. 16. Wang W, Kim SH, El-Deiry WS (2006) Small-molecule modulators of p53 family signaling and antitumor effects in p53-deficient human colon tumor xenografts. Proc Natl Acad Sci USA 103: 11003–8. 17. Shangary S, Qin D, McEachern D, Liu M, Miller RS, et al. (2008) Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc Natl Acad Sci USA 105: 3933–8. 18. Lain S, Hollick JJ, Campbell J, Staples OD, Higgins M, et al. (2008) Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 13: 454–63. 19. Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP (2009) Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer 9: 862–73. 20. Sarek G, Kurki S, Enba¨ck J, Iotzova G, Haas J, et al. (2007) Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas. J Clin Invest 117: 1019–28. 21. El-Deiry WS, Kern SE, Pietenpol JA, Kinzler KW, Vogelstein B (1992) Definition of a consensus binding site for p53. Nat Genet 1: 45–9. 22. Zhang JH, Chung TD, Oldenburg KR (1991) A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J Biomol Screen 4: 67–73. 23. Bedi A, Griffin CA, Barber JP, Vala MS, Hawkins AL, et al. (1994) Growth factor-mediated terminal differentiation of chronic myeloid leukemia. Cancer Res 54: 5535–8. 24. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, et al. (2000) Gene ontology: tool for the unification of biology. The gene ontology consortium. Nat Genet 25: 25–9. 25. Dennis G, Jr., Sherman BT, Hosack DA, Yang J, Gao W, et al. (2003) DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 4: P3. 26. Keller SA, Hernandez-Hopkins D, Vider J, Ponomarev V, Hyjek E, et al. (2006) NF-kappaB is essential for the progression of KSHV- and EBV-infected lymphomas in vivo. Blood 107: 3295–302. 27. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46: 3–26. 28. Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, et al. (1998) Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282: 1497–501. Novel p53 Pathway Activators 29. Kiviharju-af Ha¨llstro¨ m TM, Ja¨ a¨maa S, Mo¨ nkko¨ nen M, Peltonen K, Andersson LC, et al. (2007) Human prostate epithelium lacks Wee1A-mediated DNA damage-induced checkpoint enforcement. Proc Natl Acad Sci USA 104: 7211–16. 30. Palchaudhuri R, Hergenrother PJ (2007) DNA as a target for anticancer compounds: methods to determine the mode of binding and the mechanism of action. Curr Opin Biotechnol 18: 497–503. 31. Webb MR, Ebeler SE (2003) A gel electrophoresis assay for the simultaneous determination of topoisomerase I inhibition and DNA intercalation. Anal Biochem 321: 22–30. 32. Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW (1991) Participation of p53 protein in the cellular response to DNA damage. Cancer Res 51: 6304–11. 33. Hickson I, Zhao Y, Richardson CJ, Green SJ, Martin NM, et al. (2004) Identification and characterization of a novel and specific inhibitor of the ataxia- telangiectasia mutated kinase ATM. Cancer Res 64: 9152–9. 34. Zhao R, Gish K, Murphy M, Yin Y, Notterman D, et al. (2000) Analysis of p53- regulated gene expression patterns using oligonucleotide arrays. Genes Dev 14: 981–93. 35. Wei CL, Wu Q, Vega VB, Chiu KP, Ng P, et al. (2006) A global map of p53 transcription-factor binding sites in the human genome. Cell 124: 207–19. 36. Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, et al. (2006) The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313: 1929–35. 37. Hurley LH (2002) DNA and its associated processes as targets for cancer therapy. Nat Rev Cancer 2: 188–200. 38. Tse WC, Boger DL (2004) Sequence-selective DNA recognition: natural products and nature’s lessons. Chem Biol 1: 1607–17. 39. Ferguson LR, Denny WA (2007) Genotoxicity of non-covalent interactions: DNA intercalators. Mutat Res 623: 14–23. 40. Hendry LB, Mahesh VB, Bransome ED, Jr., Ewing DE (2007) Small molecule intercalation with double stranded DNA: implications for normal gene regulation and for predicting the biological efficacy and genotoxicity of drugs and other chemicals. Mutat Res 623: 53–71. 41. Boer DR, Canals A, Coll M (2009) DNA-binding drugs caught in action: the latest 3D pictures of drug-DNA complexes. Dalton Trans 3: 399–414. 42. Nitiss JL (2009) Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer 9: 338–50. 43. Ljungman M, Lane DP (2004) Transcription - guarding the genome by sensing DNA damage. Nat Rev Cancer 4: 727–37. 44. Dalton SO, Johansen C, Poulsen AH, Nørgaard M, Sørensen HT, et al. (2006) Cancer risk among users of neuroleptic medication: a population-based cohort study. Br J Cancer 95: 934–9. 45. Lin SC, Chueh SC, Hsiao CJ, Li TK, Chen TH, et al. (2007) Prazosin displays anticancer activity against human prostate cancers: targeting DNA and cell cycle. Neoplasia 9: 830–9. 46. Harris AM, Warner BW, Wilson JM, Becker A, Rowland RG, et al. (2007) Effect of alpha1-adrenoceptor antagonist exposure on prostate cancer incidence: an observational cohort study. J Urol 178: 2176–80. 47. Ye R, Goodarzi AA, Kurz EU, Saito S, Higashimoto Y, et al. (2004) The isoflavonoids genistein and quercetin activate different stress signaling pathways as shown by analysis of site-specific phosphorylation of ATM, p53 and histone H2AX. DNA Repair 3: 235–44. 48. Newman RA, Yang P, Pawlus AD, Block KI (2008) Cardiac glycosides as novel cancer therapeutic agents. Mol Interv 8: 36–49. 49. Semenza GL (2010) Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29: 625–34. PLoS ONE | www.plosone.org 11 September 2010 | Volume 5 | Issue 9 | e12996