Toxicology International (Formerly Indian Journal of Toxicology)

Open Access Open Access  Restricted Access Subscription Access
Open Access Open Access Open Access  Restricted Access Restricted Access Subscription Access

P53 and It’s Applications in Cancer Therapy


Affiliations
1 Department of Pharmacology and Toxicology, College of Veterinary Science and Animal Husbandry, Rasalpura - 453446, Mhow, Madhya Pradesh, India
2 Department of Pharmacology and Toxicology, GADVASU, Ludhiana - 141012, Punjab, India
     

   Subscribe/Renew Journal


P53 is a tumour suppressor protein encoded by the TP53 gene, which is one of the most commonly mutated gene in human and animal cancers. Missense Mutation of the p53 gene is the most prevalent genetic abnormalities which gives rise to full length p53 containing single amino acid substitution within the sequence-specific DNA binding domain (|Greenblatt et al., 1994)14. p53 plays anti-cancer role, through several mechanisms namely by activating DNA repair, initiating apoptosis and inducing growth arrest. By managing the DNA damage, p53 gene plays an important role in maintaining integrity and stability of the genome and therefore, it has been described as "the guardian of the genome". Restoring p53 function is a major step in the treatment of many cancers by following different strategies like, gene replacement therapy using wild-type p53, reactivation of p53 function, inhibition of p53-Mdm2 interaction etc. Advexin is an Adeno-p53 vector, recognized as an orphan drug by USA, Food and Drug administration in 2003, provides delivery of wild-type p53 to cancer cells and demonstrates anticancer activity following adequate expression of p53 (Nemunaitis and Nemunaitis, 2008)27. Similarly, MI-319 restores p53 functions and increases the life span of orally treated follicular lymphoma bearing animals (Mohammad et al., 2009)25. These strategies of p53-based cancer therapy differ greatly between themselves both in the mode of action and the degree of success seen in experimental models. Cancer therapy based around p53 proves to be more efficacious, especially in terms of specificity. But the innovation of successful p53-based cancer therapies is only limited by our understanding of p53 biology and the creative use of such knowledge. In future, p53-based cancer therapy can be a valuable option for the treatment of a variety of tumours in human as well as animals.

Keywords

P53/Cancer Therapy.
User
Subscription Login to verify subscription
Notifications
Font Size

  • Amaral. The role of p53 in apoptosis. Discovery Med. 2010; 9(45):145–52.

  • Bennett M, Macdonald K, Chan SW, Luzio JP, Simari R, Weissberg P. Cell surface trafficking of Fas: a rapid mechanism of p53-mediated apoptosis. Science. 1998; 282:290–3.

  • Bertholet S, Iggo R, Corradin G. Cytotoxic T lymphocyte responces to wild-type and mutant mouse p53 peptides. Eur J Immunol. 1997; 27:798–801.

  • Bottger A, Bottger V, Sparks A. Design of a synthetic Mdm2-binding mini protein that activates the p53 response in vivo. Curr Biol. 1997; 7:860–9.

  • Bunz F. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science. 1998; 282:1497–501.

  • Bykov VJ, Selivanova G, Wiman KG. Small molecules that reactivate mutant p53. Eur J Cancer. 2003; 39:1828–34.

  • Cai DW, Mukhopadhyay T, Liu YJ. Stable expression of the wild-type p53 gene in human lung-cancer cells after retrovirus mediated gene-transfer. Human Gene Ther. 1993; 4:617–24.

  • Chen J, Wu X, Lin J, Levine AJ. Mdm2 inhibits the G1 arrest and apoptosis functions of the p53 tumour suppressor protein. Mol Cell Biol. 1996; 16:2445–52.

  • Ciernik IF, Berzofsky J, Carbone DP. Mutant oncopeptide immunization induces CTL specifically lysing tumour-cells endogenously expressing the corresponding intact mutant p53. Hybridoma. 1995; 14:139–42.

  • Conseiller E, Debussche L, Landais D. CTS-1: A p53-derived chimeric tumour suppressor gene with enhanced in vitro apoptotic properties. J Clin Invest. 1998; 101:120–7.

  • Cui R, Widlund HR, Feige E, Lin JY, Wilensky DL, Igras VE, D’Orazio J, Fung CY, Schanbacher CF, Granter SR, Fisher DE. Central role of p53 in the suntan response and pathologic hyperpigmentation. Cell. 2007; 128(5):853–64.

  • Farhood H, Gao X, Son K. Cationic liposomes for direct gene-transfer in therapy of cancer and other diseases. Ann Ny Acad Sci. 1994; 716:23–35.

  • Gallagher WM, Brown R. p53-oriented cancer therapies: current progress. Annals Oncol. 1999; 10:139–50.

  • Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumour suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994; 54:4855–78.

  • Hanahan D, Weinberg RA. The hallmarks of cancer. Cell.2000; 100:57–70.

  • Howard MIC, Kershaw T, Gibb B. High efficiency gene transfer to the central nervous system of rodents and primates using herpes virus vectors lacking functional p27 and p34.5. Gene Ther. 1998; 5:1137–47.

  • Idogawa M, Ohashi T, Sasaki Y, Maruyama R, Kashima L, Suzuki H, Tokino T. Identification and analysis of large intergenic non-coding RNAs regulated by p53 family members through a genome-wide analysis of p53-binding sites. Hum Mol Genet. 2014; 23:2847–57.

  • Issaeva N, Friedler A, Bozko P, Wiman KG, Fersht AR, Selivanova G. Rescue of mutants of the tumour suppressor p53 in cancer cells by a designed peptide. Proc Nat Acad Sci. 2003; 100:13303–7.

  • Jeffers JR, Parganas E, Lee Y, Yang C, Wang J. Puma is an essential mediator of p53-dependent and independent apoptotic pathways. Cancer Cell. 2003; 4(4):321–8.

  • Joerger AC, Fersht AR. Structural biology of the tumor suppressor p53. Annu Rev Biochem. 2008; 77:557–82.

  • Koshland DE. Molecule of the year. Science. 1993; 262(5142):1953.

  • Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev. 2007; 87(1):99–163.

  • Lesoonwood LA, Kim WH, Kleinman HK. Systemic gene-therapy with p53 reduces growth and metastases of a malignant human breast cancer in nude-mice. Human Gene Ther. 1995; 6:395–405.

  • Maier B, Gluba W, Bernier B. Modulation of mammalian life span by the short isoform of p53. Genes Dev. 2004; 18(3):306–19.

  • Mohammad RM, Wu J, Azmi AS, Aboukameel A, Sosin A. An Mdm2 antagonist (MI-319) restores p53 functions and increases the life span of orally treated follicular lymphoma bearing animals. Mol. Cancer. 2009; 8:115.

  • Moroni MC, Hickman ES, Denchi EL, Caprara G. Apaf-1 is a transcriptional target for E2F and p53. Nat Cell Biol. 2001; 3(6):552–8.

  • Nemunaitis K, Nemunaitis S. Potential of Advexin: a p53 gene-replacement therapy in Li-Fraumeni syndrome. J Clin Oncol. 2008; 20:2408–18.

  • Nielsen LL, Maneval DC. p53: Tumour suppressor gene therapy for cancer. Cancer Gene Ther. 1997; 4:129–38.

  • Oconnor PM, Jackman J, Bae I. Characterization of the p53 tumour suppressor pathway in cell lines of the national cancer institute anticancer drug screen and correlations with the growth inhibitory potency of 123 anticancer agents. Cancer Res. 1997; 57:4285–300.

  • Roth JA, Cristiano RJ. Gene therapy for cancer: What have we done and where are we going? J Nat Cancer Inst. 1997; 89:21–39.

  • Sakaguchi K, Herrera JE, Saito S. DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes Dev. 1998; 12:2831–41.

  • Shangary S, Wang S. Small-molecule inhibitors of the Mdm2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. Annu Rev Pharmacol Toxicol. 2009; 49:223–41.

  • Snyder EL, Meade BR, Saenz CC, Dowdy SF. Treatment of terminal peritoneal carcinomatosis by a transducible p53-activating peptide. Proc Biol. 2004; 2:36.

  • Takashi D, Bruce SE. Induction of wild-type p53 activity in human cancer cells by ribozyme that repair mutant p53 transcripts. Future Oncol. 2000; 4(6):759–68.

  • Tamura M, Sasaki Y, Kobashi K, Takeda K, Nakagaki T, Idogawa M, Tokino T. CRKL oncogene is downregulated by p53 through miR-200s. Cancer Science. 2015; 106(7):1–8.

  • Tamura M, Sasaki Y, Koyama R, Takeda K, Idogawa M, Tokino T. Forkhead transcription factor FOXF1 is a novel target gene of the p53 family and regulates cancer cell migration and invasiveness. Oncogene. 2014; 33:4837–46.

  • Tang X, Zhu Y, Han L, Kim AL, Kopelovich L, Bickers DR, Athar M. CP-31398 restores mutant p53 tumour suppressor function and inhibits UVB-induced skin carcinogenesis in mice. J Clin Invest. 2002; 112(12):3753–64.

  • Thomas M, Massimi P, Banks L. HPV-18 E6 inhibits DNA binding activity regardless of the oligomeric state of p53 or the exact p53 recognition sequence. Oncogene. 1996; 13:471–80.

  • Vakhrusheva O, Smolka C, Gajawada P, Kostin S, Boettger T, Kubin T, Braun T. Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ Res. 2008; 102(6):703–10.

  • Vegad JL. Neoplasia. In: A text book of veterinary general pathology (2nd edn). International book publishing distributing corporation, Lucknow. 2007; 277–335.

  • Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000; 408:307–10.

  • Wade M, Li YC, Wahl GM. MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nature Reviews Cancer. 2013; 13:83–96.

  • Wang W, El-Deiry WS. Restoration of p53 to limit tumour growth. Curr Opin Oncol. 2008; 20(1):90–6.

  • Wolff JA, Malone RW, Williams P. Direct gene-transfer into mouse muscle in vivo. Science. 1990; 247:1465–8.

  • Wu GS, Burns TF, McDonald ER. KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat Genet. 1997; 17(2):141–3.

  • Wu N, Rollin J, Masse I, Lamartine J, Gidrol X. P53 regulates human keratinocytes proliferation by MYC –regulated gene network and differentiation commitment through cell adhesion-related gene network. The Journal of Biological Chemistry. 2012; 287(8):5627–38.

  • Xu L, Pirollo KF, Chang EH. Transferrin-liposome-mediated p53 sensitisation of squamous cell carcinoma of the head and neck to radiation in vitro. Human Gene Ther. 1997; 8:467–75.

  • Zhang J, Sun Q, Zhang Z, Ge S, Han ZG, Chen WT. Loss of microRNA-143/145 disturbs cellular growth and apoptosis of human epithelial cancers by impairing the MDM2-p53 feedback loop. Oncogene. 2013; 32:61–9.


Abstract Views: 412

PDF Views: 0




  • P53 and It’s Applications in Cancer Therapy

Abstract Views: 412  |  PDF Views: 0

Authors

Neetu Rajput
Department of Pharmacology and Toxicology, College of Veterinary Science and Animal Husbandry, Rasalpura - 453446, Mhow, Madhya Pradesh, India
Supriya
Department of Pharmacology and Toxicology, College of Veterinary Science and Animal Husbandry, Rasalpura - 453446, Mhow, Madhya Pradesh, India
Megha Kadam
Department of Pharmacology and Toxicology, College of Veterinary Science and Animal Husbandry, Rasalpura - 453446, Mhow, Madhya Pradesh, India
V. K. Dumka
Department of Pharmacology and Toxicology, GADVASU, Ludhiana - 141012, Punjab, India
H. S. Sandhu
Department of Pharmacology and Toxicology, GADVASU, Ludhiana - 141012, Punjab, India

Abstract


P53 is a tumour suppressor protein encoded by the TP53 gene, which is one of the most commonly mutated gene in human and animal cancers. Missense Mutation of the p53 gene is the most prevalent genetic abnormalities which gives rise to full length p53 containing single amino acid substitution within the sequence-specific DNA binding domain (|Greenblatt et al., 1994)14. p53 plays anti-cancer role, through several mechanisms namely by activating DNA repair, initiating apoptosis and inducing growth arrest. By managing the DNA damage, p53 gene plays an important role in maintaining integrity and stability of the genome and therefore, it has been described as "the guardian of the genome". Restoring p53 function is a major step in the treatment of many cancers by following different strategies like, gene replacement therapy using wild-type p53, reactivation of p53 function, inhibition of p53-Mdm2 interaction etc. Advexin is an Adeno-p53 vector, recognized as an orphan drug by USA, Food and Drug administration in 2003, provides delivery of wild-type p53 to cancer cells and demonstrates anticancer activity following adequate expression of p53 (Nemunaitis and Nemunaitis, 2008)27. Similarly, MI-319 restores p53 functions and increases the life span of orally treated follicular lymphoma bearing animals (Mohammad et al., 2009)25. These strategies of p53-based cancer therapy differ greatly between themselves both in the mode of action and the degree of success seen in experimental models. Cancer therapy based around p53 proves to be more efficacious, especially in terms of specificity. But the innovation of successful p53-based cancer therapies is only limited by our understanding of p53 biology and the creative use of such knowledge. In future, p53-based cancer therapy can be a valuable option for the treatment of a variety of tumours in human as well as animals.

Keywords


P53/Cancer Therapy.

References





DOI: https://doi.org/10.22506/ti%2F2015%2Fv22%2Fi2%2F137644