Cancer Chemotherapy and Pharmacology

, Volume 83, Issue 1, pp 1–15 | Cite as

Awakening the “guardian of genome”: reactivation of mutant p53

  • Akshay Binayke
  • Sarthak Mishra
  • Prabhat Suman
  • Suman Das
  • Harish ChanderEmail author
Review Article


The role of tumor suppressor protein p53 is undeniable in the suppression of cancer upon oncogenic stress. It induces diverse conditions such as cell-cycle arrest, cell death, and senescence to protect the cell from carcinogenesis. The rate of mutations in p53 gene nearly accounts for 50% of the human cancers. Upon mutations, the conformation gets altered and becomes non-native. Mutant p53 displays long half-life and accumulates in the nucleus and interacts with oncoproteins to promote carcinogenesis and these interactions present a formidable challenge for clinicians in therapy of the disease. Variety of approaches have been developed, through which native-like function of p53 can be restored, such as restoration of the native-like structure of p53, activating the p53 family members, etc. Modern scientific techniques have led to the discovery of a variety of molecules to reactivate mutant p53 and restore its transcriptional activity. These compounds include small molecules, various peptides, and phytochemicals. In this review article, we comprehensively discuss these molecules to reactivate mutant p53 to restore the normal function with a particular focus on molecular mechanisms.


Mutant p53 Reactivation Gain-of-function Cancer therapy Drug target 



We acknowledge Department of Science and Technology-Science and Engineering Research Board (DST-SERB), Government of India for extramural Research Grant (EMR/2015/000761) to H. C. and Central University of Punjab, Bathinda, India for additional support.


This study was funded by the Department of Science and Technology-Science and Engineering Research Board, (DST-SERB), Government of India (EMR/2015/000761).

Compliance with ethical standards

Conflict of interest

Author AB declares that he has no conflict of interest. Author SM declares that he has no conflict of interest. Author PS declares that he has no conflict of interest. Author SD declares that he has no conflict of interest. Author HC declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Menendez D, Inga A, Resnick MA (2009) The expanding universe of p53 targets. Nat Rev Cancer 9(10):724–737Google Scholar
  2. 2.
    Goldstein I, Marcel V, Olivier M, Oren M, Rotter V, Hainaut P (2011) Understanding wild-type and mutant p53 activities in human cancer: new landmarks on the way to targeted therapies. Cancer Gene Ther 18(1):2–11. Google Scholar
  3. 3.
    Muller PAJ, Vousden KH, Norman JC (2011) p53 and its mutants in tumor cell migration and invasion. J Cell Biol 192(2):209–218. Google Scholar
  4. 4.
    Brown CJ, Cheok CF, Verma CS, Lane DP Reactivation of p53: from peptides to small molecules. Trends Pharmacol Sci 32(1):53–62.
  5. 5.
    Stindt MH, Muller PA, Ludwig RL, Kehrloesser S, Dotsch V, Vousden KH (2015) Functional interplay between MDM2, p63/p73 and mutant p53. Oncogene 34(33):4300–4310. Google Scholar
  6. 6.
    Sherman M, Gabai V, O’Callaghan C, Yaglom J (2007) Molecular chaperones regulate p53 and suppress senescence programs. FEBS Lett 581(19):3711–3715. Google Scholar
  7. 7.
    Muller PAJ, Vousden KH (2013) p53 mutations in cancer. Nat Cell Biol 15(1):2–8Google Scholar
  8. 8.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253(5015):49–53Google Scholar
  9. 9.
    Brosh R, Rotter V (2009) When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer 9(10):701–713. Google Scholar
  10. 10.
    Cooks T, Pateras IS, Tarcic O, Solomon H, Schetter AJ, Wilder S, Lozano G, Pikarsky E, Forshew T, Rozenfeld N (2013) Mutant p53 prolongs NF-κB activation and promotes chronic inflammation and inflammation-associated colorectal cancer. Cancer Cell 23(5):634–646Google Scholar
  11. 11.
    Sampath J, Sun D, Kidd VJ, Grenet J, Gandhi A, Shapiro LH, Wang Q, Zambetti GP, Schuetz JD (2001) Mutant p53 cooperates with ETS and selectively up-regulates human MDR1 not MRP1. J Biol Chem 276(42):39359–39367Google Scholar
  12. 12.
    Lang GA, Iwakuma T, Suh YA, Liu G, Rao VA, Parant JM, Valentin-Vega YA, Terzian T, Caldwell LC, Strong LC, El-Naggar AK, Lozano G (2004) Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell 119(6):861–872. Google Scholar
  13. 13.
    Terzian T, Suh YA, Iwakuma T, Post SM, Neumann M, Lang GA, Van Pelt CS, Lozano G (2008) The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss. Genes Dev 22(10):1337–1344. Google Scholar
  14. 14.
    Parrales A, Iwakuma T (2015) Targeting oncogenic mutant p53 for cancer therapy. Front Oncol 5:288. Google Scholar
  15. 15.
    Martins CP, Brown-Swigart L, Evan GI (2006) Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 127(7):1323–1334. Google Scholar
  16. 16.
    Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T (2007) Restoration of p53 function leads to tumour regression in vivo. Nature 445(7128):661–665. Google Scholar
  17. 17.
    Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW (2007) Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445(7128):656–660. Google Scholar
  18. 18.
    Alexandrova EM, Yallowitz AR, Li D, Xu S, Schulz R, Proia DA, Lozano G, Dobbelstein M, Moll UM (2015) Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment. Nature 523(7560):352–356. Google Scholar
  19. 19.
    Freed-Pastor WA, Mizuno H, Zhao X, Langerod A, Moon SH, Rodriguez-Barrueco R, Barsotti A, Chicas A, Li W, Polotskaia A, Bissell MJ, Osborne TF, Tian B, Lowe SW, Silva JM, Borresen-Dale AL, Levine AJ, Bargonetti J, Prives C (2012) Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell 148(1–2):244–258. Google Scholar
  20. 20.
    Masciarelli S, Fontemaggi G, Di Agostino S, Donzelli S, Carcarino E, Strano S, Blandino G (2014) Gain-of-function mutant p53 downregulates miR-223 contributing to chemoresistance of cultured tumor cells. Oncogene 33(12):1601–1608. Google Scholar
  21. 21.
    Weisz L, Oren M, Rotter V (2007) Transcription regulation by mutant p53. Oncogene 26(15):2202–2211. Google Scholar
  22. 22.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70Google Scholar
  23. 23.
    Selivanova G, Kawasaki T, Ryabchenko L, Wiman KG (1998) Reactivation of mutant p53: a new strategy for cancer therapy. Semin Cancer Biol 8(5):369–378Google Scholar
  24. 24.
    Zhang W, Guo XY, Hu GY, Liu WB, Shay JW, Deisseroth AB (1994) A temperature-sensitive mutant of human p53. EMBO J 13(11):2535–2544Google Scholar
  25. 25.
    Friedler A, Hansson LO, Veprintsev DB, Freund SM, Rippin TM, Nikolova PV, Proctor MR, Rudiger S, Fersht AR (2002) A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants. Proc Natl Acad Sci USA 99(2):937–942. Google Scholar
  26. 26.
    Selivanova G, Iotsova V, Okan I, Fritsche M, Strom M, Groner B, Grafstrom RC, Wiman KG (1997) Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain. Nat Med 3(6):632–638Google Scholar
  27. 27.
    Bykov VJN, Issaeva N, Zache N, Shilov A, Hultcrantz M, Bergman J, Selivanova G, Wiman KG (2005) Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs. J Biol Chem 280(34):30384–30391. Google Scholar
  28. 28.
    Liu WL, Midgley C, Stephen C, Saville M, Lane DP (2001) Biological significance of a small highly conserved region in the N terminus of the p53 tumour suppressor protein. J Mol Biol 313(4):711–731. Google Scholar
  29. 29.
    Nikolova PV, Wong KB, DeDecker B, Henckel J, Fersht AR (2000) Mechanism of rescue of common p53 cancer mutations by second-site suppressor mutations. EMBO J 19(3):370–378. Google Scholar
  30. 30.
    Bykov VJ, Wiman KG (2014) Mutant p53 reactivation by small molecules makes its way to the clinic. FEBS Lett 588(16):2622–2627. Google Scholar
  31. 31.
    Foster BA, Coffey HA, Morin MJ, Rastinejad F (1999) Pharmacological rescue of mutant p53 conformation and function. Science 286(5449):2507–2510Google Scholar
  32. 32.
    Wang W, Takimoto R, Rastinejad F, El-Deiry WS (2003) Stabilization of p53 by CP-31398 inhibits ubiquitination without altering phosphorylation at serine 15 or 20 or MDM2 binding. Mol Cell Biol 23(6):2171–2181Google Scholar
  33. 33.
    Rao CV, Swamy MV, Patlolla JMR, Kopelovich L (2008) Suppression of familial adenomatous polyposis by CP-31398, a TP53 modulator in APCmin/+ mice. Cancer Res 68(18):7670–7675. Google Scholar
  34. 34.
    Tang X, Zhu Y, Han L, Kim AL, Kopelovich L, Bickers DR, Athar M (2007) CP-31398 restores mutant p53 tumor suppressor function and inhibits UVB-induced skin carcinogenesis in mice. J Clin Investig 117(12):3753–3764. Google Scholar
  35. 35.
    Fiorini C, Menegazzi M, Padroni C, Dando I, Dalla Pozza E, Gregorelli A, Costanzo C, Palmieri M, Donadelli M (2013) Autophagy induced by p53-reactivating molecules protects pancreatic cancer cells from apoptosis. Apoptosis 18(3):337–346. Google Scholar
  36. 36.
    Hainaut P, Milner J (1993) Redox modulation of p53 conformation and sequence-specific DNA binding in vitro. Can Res 53(19):4469–4473Google Scholar
  37. 37.
    Zache N, Lambert JMR, Rökaeus N, Shen J, Hainaut P, Bergman J, Wiman KG, Bykov VJN (2008) Mutant p53 targeting by the low molecular weight compound STIMA-1. Mol Oncol 2(1):70–80. Google Scholar
  38. 38.
    Bykov VJ, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P, Bergman J, Wiman KG, Selivanova G (2002) Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med 8(3):282–288. Google Scholar
  39. 39.
    Duffy MJ, Synnott NC, McGowan PM, Crown J, O’Connor D, Gallagher WM (2014) p53 as a target for the treatment of cancer. Cancer Treat Rev 40(10):1153–1160. Google Scholar
  40. 40.
    Zandi R, Selivanova G, Christensen CL, Gerds TA, Willumsen BM, Poulsen HS (2011) PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53. Clin Cancer Res 17(9):2830–2841. Google Scholar
  41. 41.
    Fransson A, Glaessgen D, Alfredsson J, Wiman KG, Bajalica-Lagercrantz S, Mohell N (2016) Strong synergy with APR-246 and DNA-damaging drugs in primary cancer cells from patients with TP53 mutant high-grade serous ovarian cancer. J Ovarian Res 9(1):27. Google Scholar
  42. 42.
    Lambert JM, Gorzov P, Veprintsev DB, Söderqvist M, Segerbäck D, Bergman J, Fersht AR, Hainaut P, Wiman KG, Bykov VJ (2009) PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer cell 15(5):376–388Google Scholar
  43. 43.
    Krayem M, Journe F, Wiedig M, Morandini R, Najem A, Sales F, van Kempen LC, Sibille C, Awada A, Marine JC, Ghanem G (2016) p53 Reactivation by PRIMA-1(Met) (APR-246) sensitises (V600E/K)BRAF melanoma to vemurafenib. Eur J Cancer (Oxford England: 1990) 55:98–110. Google Scholar
  44. 44.
    Rao CV, Patlolla JM, Qian L, Zhang Y, Brewer M, Mohammed A, Desai D, Amin S, Lightfoot S, Kopelovich L (2013) Chemopreventive effects of the p53-modulating agents CP-31398 and Prima-1 in tobacco carcinogen-induced lung tumorigenesis in A/J mice. Neoplasia (New York, NY) 15(9):1018–1027Google Scholar
  45. 45.
    Bykov VJ, Zhang Q, Zhang M, Ceder S, Abrahmsen L, Wiman KG (2016) Targeting of mutant p53 and the cellular redox balance by APR-246 as a strategy for efficient cancer therapy. Front Oncol 6:21. Google Scholar
  46. 46.
    Nahi H, Merup M, Lehmann S, Bengtzen S, Möllgård L, Selivanova G, Wiman K, Paul C (2006) PRIMA-1 induces apoptosis in acute myeloid leukaemia cells with p53 gene deletion. Br J Haematol 132(2):230–236Google Scholar
  47. 47.
    Lehmann S, Bykov VJN, Ali D, Andrén O, Cherif H, Tidefelt U, Uggla B, Yachnin J, Juliusson G, Moshfegh A, Paul C, Wiman KG, Andersson P-O (2012) Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J Clin Oncol 30(29):3633–3639. Google Scholar
  48. 48.
    Saha MN, Chen Y, Chen MH, Chen G, Chang H (2014) Small molecule MIRA-1 induces in vitro and in vivo anti-myeloma activity and synergizes with current anti-myeloma agents. Br J Cancer 110(9):2224–2231. Google Scholar
  49. 49.
    Boeckler FM, Joerger AC, Jaggi G, Rutherford TJ, Veprintsev DB, Fersht AR (2008) Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Proc Natl Acad Sci USA 105(30):10360–10365. Google Scholar
  50. 50.
    Rauf SMA, Endou A, Takaba H, Miyamoto A (2013) Effect of Y220C mutation on p53 and its rescue mechanism: a computer chemistry approach. Protein J 32(1):68–74. Google Scholar
  51. 51.
    Liu X, Wilcken R, Joerger AC, Chuckowree IS, Amin J, Spencer J, Fersht AR (2013) Small molecule induced reactivation of mutant p53 in cancer cells. Nucleic Acids Res 41(12):6034–6044. Google Scholar
  52. 52.
    Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef LG, Masucci M, Pramanik A, Selivanova G (2004) Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med 10(12):1321–1328. Google Scholar
  53. 53.
    Burmakin M, Shi Y, Hedstrom E, Kogner P, Selivanova G (2013) Dual targeting of wild-type and mutant p53 by small molecule RITA results in the inhibition of N-Myc and key survival oncogenes and kills neuroblastoma cells in vivo and in vitro. Clin Cancer Res 19(18):5092–5103. Google Scholar
  54. 54.
    Grinkevich VV, Nikulenkov F, Shi Y, Enge M, Bao W, Maljukova A, Gluch A, Kel A, Sangfelt O, Selivanova G (2009) Ablation of key oncogenic pathways by RITA-reactivated p53 is required for efficient apoptosis. Cancer Cell 15(5):441–453. Google Scholar
  55. 55.
    Roh JL, Ko JH, Moon SJ, Ryu CH, Choi JY, Koch WM (2012) The p53-reactivating small-molecule RITA enhances cisplatin-induced cytotoxicity and apoptosis in head and neck cancer. Cancer Lett 325(1):35–41. Google Scholar
  56. 56.
    Zhao CY, Grinkevich V, Nikulenkov F, Bao W, Selivanova G (2010) Rescue of the apoptotic-inducing function of mutant p53 by small molecule RITA. Cell Cycle 9(9):1847–1855. Google Scholar
  57. 57.
    Zhu H, Abulimiti M, Liu H, Su XJ, Liu CH, Pei HP (2015) RITA enhances irradiation-induced apoptosis in p53-defective cervical cancer cells via upregulation of IRE1alpha/XBP1 signaling. Oncol Rep 34(3):1279–1288. Google Scholar
  58. 58.
    Friedler A, DeDecker BS, Freund SM, Blair C, Rudiger S, Fersht AR (2004) Structural distortion of p53 by the mutation R249S and its rescue by a designed peptide: implications for “mutant conformation”. J Mol Biol 336(1):187–196Google Scholar
  59. 59.
    Demma M, Maxwell E, Ramos R, Liang L, Li C, Hesk D, Rossman R, Mallams A, Doll R, Liu M, Seidel-Dugan C, Bishop WR, Dasmahapatra B (2010) SCH529074, a small molecule activator of mutant p53, which binds p53 DNA Binding domain (DBD), restores growth-suppressive function to mutant p53 and interrupts HDM2-mediated ubiquitination of wild type p53. J Biol Chem 285(14):10198–10212. Google Scholar
  60. 60.
    Margalit O, Simon AJ, Yakubov E, Puca R, Yosepovich A, Avivi C, Jacob-Hirsch J, Gelernter I, Harmelin A, Barshack I, Rechavi G, D’Orazi G, Givol D, Amariglio N (2012) Zinc supplementation augments in vivo antitumor effect of chemotherapy by restoring p53 function. Int J Cancer 131(4):E562–E568. Google Scholar
  61. 61.
    Pintus SS, Ivanisenko NV, Demenkov PS, Ivanisenko TV, Ramachandran S, Kolchanov NA, Ivanisenko VA (2013) The substitutions G245C and G245D in the Zn(2+)-binding pocket of the p53 protein result in differences of conformational flexibility of the DNA-binding domain. J Biomol Struct Dyn 31(1):78–86. Google Scholar
  62. 62.
    Puca R, Nardinocchi L, Porru M, Simon AJ, Rechavi G, Leonetti C, Givol D, D’Orazi G (2011) Restoring p53 active conformation by zinc increases the response of mutant p53 tumor cells to anticancer drugs. Cell Cycle 10(10):1679–1689. Google Scholar
  63. 63.
    Yu X, Vazquez A, Levine AJ, Carpizo DR (2012) Allele-specific p53 mutant reactivation. Cancer Cell 21(5):614–625. Google Scholar
  64. 64.
    Yu X, Blanden AR, Narayanan S, Jayakumar L, Lubin D, Augeri D, Kimball SD, Loh SN, Carpizo DR (2014) Small molecule restoration of wildtype structure and function of mutant p53 using a novel zinc-metallochaperone based mechanism. Oncotarget 5(19):8879Google Scholar
  65. 65.
    Blanden AR, Yu X, Wolfe AJ, Gilleran JA, Augeri DJ, O’Dell RS, Olson EC, Kimball SD, Emge TJ, Movileanu L, Carpizo DR, Loh SN (2015) Synthetic metallochaperone ZMC1 rescues mutant p53 conformation by transporting zinc into cells as an ionophore. Mol Pharmacol 87(5):825–831. Google Scholar
  66. 66.
    Garufi A, Trisciuoglio D, Porru M, Leonetti C, Stoppacciaro A, D’Orazi V, Avantaggiati M, Crispini A, Pucci D, D’Orazi G (2013) A fluorescent curcumin-based Zn(II)-complex reactivates mutant (R175H and R273H) p53 in cancer cells. J Exp Clin Cancer Res CR 32:72. Google Scholar
  67. 67.
    Garufi A, Pucci D, D’Orazi V, Cirone M, Bossi G, Avantaggiati ML, D’Orazi G (2014) Degradation of mutant p53H175 protein by Zn(II) through autophagy. Cell Death Dis 5:e1271. Google Scholar
  68. 68.
    Garufi A, D’Orazi V, Crispini A, D’Orazi G (2015) Zn(II)-curc targets p53 in thyroid cancer cells. Int J Oncol 47(4):1241–1248. Google Scholar
  69. 69.
    Lee KW, Bode AM, Dong Z (2011) Molecular targets of phytochemicals for cancer prevention. Nat Rev Cancer 11(3):211–218.
  70. 70.
    Singh S, Sharma B, Kanwar SS, Kumar A (2016) Lead phytochemicals for anticancer drug development. Front Plant Sci 7:1667. Google Scholar
  71. 71.
    Wang H, Khor TO, Shu L, Su Z, Fuentes F, Lee J-H, Kong A-NT (2012) Plants against cancer: a review on natural phytochemicals in preventing and treating cancers and their druggability. Anti Cancer Agents Med Chem 12(10):1281–1305Google Scholar
  72. 72.
    Aggarwal M, Saxena R, Sinclair E, Fu Y, Jacobs A, Dyba M, Wang X, Cruz I, Berry D, Kallakury B, Mueller SC, Agostino SD, Blandino G, Avantaggiati ML, Chung FL (2016) Reactivation of mutant p53 by a dietary-related compound phenethyl isothiocyanate inhibits tumor growth. Cell Death Differ. Google Scholar
  73. 73.
    Basak D, Punganuru SR, Srivenugopal KS (2016) Piperlongumine exerts cytotoxic effects against cancer cells with mutant p53 proteins at least in part by restoring the biological functions of the tumor suppressor. Int J Oncol 48(4):1426–1436. Google Scholar
  74. 74.
    Mori A, Lehmann S, Kelly J, Kumagai T, Desmond JC, Pervan M, McBride WH, Kizaki M, Koeffler HP (2006) Capsaicin, a component of red peppers, inhibits the growth of androgen-independent, p53 mutant prostate cancer cells. Can Res 66(6):3222Google Scholar
  75. 75.
    Wang X, Di Pasqua AJ, Govind S, McCracken E, Hong C, Mi L, Mao Y, Wu JY, Tomita Y, Woodrick JC, Fine RL, Chung FL (2011) Selective depletion of mutant p53 by cancer chemopreventive isothiocyanates and their structure-activity relationships. J Med Chem 54(3):809–816. Google Scholar
  76. 76.
    A study of the effects of PEITC on oral cells with mutant p53.
  77. 77.
    Clark R, Lee S-H (2016) Anticancer properties of capsaicin against human cancer. Anticancer Res 36(3):837–843Google Scholar
  78. 78.
    Kuo YC, Kuo PL, Hsu YL, Cho CY, Lin CC (2006) Ellipticine induces apoptosis through p53-dependent pathway in human hepatocellular carcinoma HepG2 cells. Life Sci 78(22):2550–2557. Google Scholar
  79. 79.
    Peng Y, Li C, Chen L, Sebti S, Chen J (2003) Rescue of mutant p53 transcription function by ellipticine. Oncogene 22(29):4478–4487. Google Scholar
  80. 80.
    Kuo P-L, Hsu Y-L, Chang C-H, Lin C-C (2005) The mechanism of ellipticine-induced apoptosis and cell cycle arrest in human breast MCF-7 cancer cells. Cancer Lett 223(2):293–301Google Scholar
  81. 81.
    Wang F, Liu J, Robbins D, Morris K, Sit A, Liu Y-Y, Zhao Y (2011) Mutant p53 exhibits trivial effects on mitochondrial functions which can be reactivated by ellipticine in lymphoma cells. Apoptosis 16(3):301–310. Google Scholar
  82. 82.
    Raj L, Ide T, Gurkar AU, Foley M, Schenone M, Li X, Tolliday NJ, Golub TR, Carr SA, Shamji AF, Stern AM, Mandinova A, Schreiber SL, Lee SW (2011) Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 475(7355):231–234. Google Scholar
  83. 83.
    Punganuru SR, Madala HR, Venugopal SN, Samala R, Mikelis C, Srivenugopal KS (2016) Design and synthesis of a C7-aryl piperlongumine derivative with potent antimicrotubule and mutant p53-reactivating properties. Eur J Med Chem 107:233–244. Google Scholar
  84. 84.
    Issaeva N, Friedler A, Bozko P, Wiman KG, Fersht AR, Selivanova G (2003) Rescue of mutants of the tumor suppressor p53 in cancer cells by a designed peptide. Proc Natl Acad Sci USA 100(23):13303–13307. Google Scholar
  85. 85.
    Tal P, Eizenberger S, Cohen E, Goldfinger N, Pietrokovski S, Oren M, Rotter V (2016) Cancer therapeutic approach based on conformational stabilization of mutant p53 protein by small peptides. Oncotarget 7(11):11817–11837. Google Scholar
  86. 86.
    Guida E, Bisso A, Fenollar-Ferrer C, Napoli M, Anselmi C, Girardini JE, Carloni P, Del Sal G (2008) Peptide aptamers targeting mutant p53 induce apoptosis in tumor cells. Cancer Res 68(16):6550–6558. Google Scholar
  87. 87.
    Prabhu V, Hong B, Allen J, Zhang S, Lulla A, Dicker D, El-Deiry W (2016) Small molecule prodigiosin restores p53 tumor suppressor activity in chemoresistant colorectal cancer stem cells via c-Jun-mediated ΔNp73 inhibition and p73 activation. Cancer Res 76(7):1989–1999. Google Scholar
  88. 88.
    Darshan N, Manonmani HK (2015) Prodigiosin and its potential applications. J Food Sci Technol 52(9):5393–5407. Google Scholar
  89. 89.
    Hong B, Prabhu VV, Zhang S, van den Heuvel AP, Dicker DT, Kopelovich L, El-Deiry WS (2014) Prodigiosin rescues deficient p53 signaling and antitumor effects via upregulating p73 and disrupting its interaction with mutant p53. Cancer Res 74(4):1153–1165. Google Scholar
  90. 90.
    Tiwary R, Yu W, Sanders BG, Kline K (2011) alpha-TEA cooperates with chemotherapeutic agents to induce apoptosis of p53 mutant, triple-negative human breast cancer cells via activating p73. Breast Cancer Res BCR 13(1):R1. Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Laboratory of Molecular Medicine, Department of Human Genetics and Molecular Medicine, School of Health SciencesCentral University of PunjabBathindaIndia

Personalised recommendations