ARTICLE INFO

Article Type

Analytic Review

Authors

Noori-Daloii   M.R. (* )
Abdollahzade   R. (1 )






(* ) Medical Genetics Department, Medicine Faculty, Tehran University of Medical sciences, Tehran, Iran
(1 ) Medical Genetics Department, Medicine Faculty, Tehran University of Medical sciences, Tehran, Iran

Correspondence

Address: No. 24, Raja’ei 13th, Raja’ei Street, Ferdows, South Khorasan, Iran. Postal Code: 9771996136
Phone: +985342222801
Fax: +985342222806
m35tabey@gmail.com

Article History

Received:  August  3, 2014
Accepted:  September 5, 2014
ePublished:  September 23, 2014

BRIEF TEXT


… [1-3] Being discovered as oncogene [4] and especially after it had been re-discovered as a tumor suppressive gene [5, 6], p53 is known as a very important item in cancer treatment [7, 8]. Some aspects of p53 are regulation of gene expression as a transcription factor, interaction with Protein TATA Binding (PTB), cell cycle control monitoring, maintaining genomic monitoring and response to DNA damage and repairing the damaged DNA and apoptosis induction, development negative regulating, and simultaneous possession of tumor inhibition and oncogenic characteristics. Due to multiple functions in activating proteins involved in DNA repair, inducing cell cycle inhibition in the control point G1/S, and inducing apoptosis in case of irreversible DNA damages, p53 protein is known as an anti-cancer gene (Fig. 1) … [9-25].

Non-declared

The aim of this study was to investigate the recent developments concerning p53 and especially its role in apoptosis, as well as some orientations towards p53 targeting and its regulators in cancer treatment.

This is a review article.

Non-declared

Non-declared

Non-declared

Main treatment approaches in p53 targeting are activating natural p53, temporary inhibition of natural p53 (to protect non-tumor cells against ray chemotherapy), and reactivating the mutant p53 to either its reactivation in tumor cells or selective killing of cancer cells with mutant p53 (Fig. 2). Natural p53 targeting to activate it is the utilization of ray chemotherapy to activate natural p53, the utilization of gene therapy to introduce natural p53 or modified adenovirus to kill cancer cells with mutant p53, and the utilization of the synthetic peptides or non-genotoxic small molecules to activate natural p53. In chemotherapy, cells or tumors carrying natural p53 are more sensitive to radiation and medication [26]. Mutant p53 leads to resistance against ray chemotherapy in patients with ovary, breast, stomach, and intestines cancers. Cancer cells with natural p53 are usually more sensitive to radiation and medication [27, 28]. Patients with breast cancer with a mutant p53 being defective in transcription show better response to ray chemotherapy than patients with natural p53 [29]. The colon cancer cells with removed p53 are more sensitive to DNA-damaging agent and Doxorubicin, while they show more resistance against 5-fluorouracil antimetabolite medication [30]. … [31] In gene therapy and during implementation of natural p53 gene into the cancer cells, the natural p53 gene enters into human pulmonary tumor cells and inhibits tumor in vitro and in vivo growths. Through human natural p53 transferring by the defective adenoviruses (Ad-p53), gene therapy has been used to more efficient transfer with lower toxicity in pre-clinical and clinical levels and through inducing growth stop and inducing apoptosis, it shows highly effective anti-cancer activity [32, 33]. … [34] Advexin/Gendicine is highly effective in esophagus, head and neck, and lung cancers treatment, lonely or in combination with chemotherapy or radiotherapy [7, 35]. … [36, 37] Pre-clinical studies show powerful anti-tumor activity of ONYX-015 as in vitro and in vivo in removing cancer cells with mutant p53 by adenoviruses, especially if it was in a composition with ray chemotherapy treatment [38]. … [39] In targeting the negative regulators of p53 to activate it, Mdm2 oncogene activity is due to its inhibition effect on p53 [40]. Therefore, in this sub-set of human cancers, Mdm2 inhibition should lead to p53 reactivation and induced cell death. To this end, there are three approaches including intervention in reactions between Mdm2 and p53 by synthetic peptides or monoclonal antibodies, inhibition of the activity of E3- ubiquitin ligase of Mdm2, and increase in the levels of Mdm2 using antisense oligonucleotides or siRNA [41]. … [42] In the destruction of Mdm2-p53 interaction by small molecules, different classes of compositions separated in structure can intervene in Mdm2-p53 interaction [43], of which the most important are the nutlins, benzodiazepinedions, and Mdm2 inhibitors (MI) derived from the spiro-oxindoles [44-50]. Concerning E3- ubiquitin ligase of Mdm2, HLI98C has the highest effectiveness on the cancer cells with natural p53, despite the fact that it shows p53-independent toxicity on the cells [51, 52]. In cancer treatment using Mdm2 inhibitors, two important points should be noticed. Firstly, there are crucial side effects in the natural cells due to p53 induction caused by Mdm2 inhibition. Secondly, at the post-treatment stage, by the compositions, p53 activation leads to Mdm2 protein integration. Besides p53, p73, p63, E2F1, and HIF1a proteins are targeted by Mdm2 protein [53]. Mdm2 leads to XIAP integration and apoptosis inhibition [54]. … [55] Deacetylation of p53 in lysine-382 by SirT1 leads to p53 inactivation and instability. Therefore, SirT1 enzyme acts as a negative regulator of p53 and through its inhibition by special medications, it is possible to increase the activity of natural p53 [56, 57]. … [58] Tenovin-1 and Tenovin-6 are the most important SirT1/SirT2 inhibitors. In targeting natural p53 to inhibit it temporarily, the side effects should be reduced by p53 temporary inhibition in the natural cells during treatment of tumors with defective p53 [59]. PFT-α and PFT-μ are two classes of small molecules that inhibit transcription activity of p53 and its ability to connect to mitochondria. The groups can be used in the clinical utilization in composition with the drug-ray in cancer treatment [60]. In p53 reactivating, in targeting the mutant p53 to restore its activity, the utilization of the synthetic peptides or small molecules, which help proper spatial structure folding of p53 and include CDB3, CP-31398, PRIMA-1, MIRA-1, Ellipticine, WR-1065, and p53R3, is one of the main approaches to restore the mutant p53 activity [55, 61-73]. … [74, 75] In the targeting of the mutant p53 to kill the cells containing it, concerning p53, the utilization of the synthetic lethality to recognize the chemical compounds selectively carrying cancer cells with mutant p53 is very crucial in discovering a new class of anti-cancer medications (Fig. 3). Paclitaxel, Metformin, UCN01, and PD0166285 are some synthetic lethality medications of p53 [76-79]. … [80]

Non-declared

Non-declared

Non-declared

Regarding its important role to inhibit carcinogenesis, p53 is one of the main medication targets to heal cancers. Based on the type of genetic changes in p53 in healthy and cancer cells, a composition of different medications can be used. In addition, through better understanding of messaging paths with p53, new upstream or downstream proteins might be discovered, in order to act as targets for new medications.

Non-declared

Non-declared

Non-declared

Non-declared

TABLES and CHARTS

Show attach file
… [1-3] Being discovered as oncogene [4] and especially after it had been re-discovered as a tumor suppressive gene [5, 6], p53 is known as a very important item in cancer treatment [7, 8]. Some aspects of p53 are regulation of gene expression as a transcription factor, interaction with Protein TATA Binding (PTB), cell cycle control monitoring, maintaining genomic monitoring and response to DNA damage and repairing the damaged DNA and apoptosis induction, development negative regulating, and simultaneous possession of tumor inhibition and oncogenic characteristics. Due to multiple functions in activating proteins involved in DNA repair, inducing cell cycle inhibition in the control point G1/S, and inducing apoptosis in case of irreversible DNA damages, p53 protein is known as an anti-cancer gene (Fig. 1) … [9-25].

Non-declared

The aim of this study was to investigate the recent developments concerning p53 and especially its role in apoptosis, as well as some orientations towards p53 targeting and its regulators in cancer treatment.

This is a review article.

Non-declared

Non-declared

Non-declared

Main treatment approaches in p53 targeting are activating natural p53, temporary inhibition of natural p53 (to protect non-tumor cells against ray chemotherapy), and reactivating the mutant p53 to either its reactivation in tumor cells or selective killing of cancer cells with mutant p53 (Fig. 2). Natural p53 targeting to activate it is the utilization of ray chemotherapy to activate natural p53, the utilization of gene therapy to introduce natural p53 or modified adenovirus to kill cancer cells with mutant p53, and the utilization of the synthetic peptides or non-genotoxic small molecules to activate natural p53. In chemotherapy, cells or tumors carrying natural p53 are more sensitive to radiation and medication [26]. Mutant p53 leads to resistance against ray chemotherapy in patients with ovary, breast, stomach, and intestines cancers. Cancer cells with natural p53 are usually more sensitive to radiation and medication [27, 28]. Patients with breast cancer with a mutant p53 being defective in transcription show better response to ray chemotherapy than patients with natural p53 [29]. The colon cancer cells with removed p53 are more sensitive to DNA-damaging agent and Doxorubicin, while they show more resistance against 5-fluorouracil antimetabolite medication [30]. … [31] In gene therapy and during implementation of natural p53 gene into the cancer cells, the natural p53 gene enters into human pulmonary tumor cells and inhibits tumor in vitro and in vivo growths. Through human natural p53 transferring by the defective adenoviruses (Ad-p53), gene therapy has been used to more efficient transfer with lower toxicity in pre-clinical and clinical levels and through inducing growth stop and inducing apoptosis, it shows highly effective anti-cancer activity [32, 33]. … [34] Advexin/Gendicine is highly effective in esophagus, head and neck, and lung cancers treatment, lonely or in combination with chemotherapy or radiotherapy [7, 35]. … [36, 37] Pre-clinical studies show powerful anti-tumor activity of ONYX-015 as in vitro and in vivo in removing cancer cells with mutant p53 by adenoviruses, especially if it was in a composition with ray chemotherapy treatment [38]. … [39] In targeting the negative regulators of p53 to activate it, Mdm2 oncogene activity is due to its inhibition effect on p53 [40]. Therefore, in this sub-set of human cancers, Mdm2 inhibition should lead to p53 reactivation and induced cell death. To this end, there are three approaches including intervention in reactions between Mdm2 and p53 by synthetic peptides or monoclonal antibodies, inhibition of the activity of E3- ubiquitin ligase of Mdm2, and increase in the levels of Mdm2 using antisense oligonucleotides or siRNA [41]. … [42] In the destruction of Mdm2-p53 interaction by small molecules, different classes of compositions separated in structure can intervene in Mdm2-p53 interaction [43], of which the most important are the nutlins, benzodiazepinedions, and Mdm2 inhibitors (MI) derived from the spiro-oxindoles [44-50]. Concerning E3- ubiquitin ligase of Mdm2, HLI98C has the highest effectiveness on the cancer cells with natural p53, despite the fact that it shows p53-independent toxicity on the cells [51, 52]. In cancer treatment using Mdm2 inhibitors, two important points should be noticed. Firstly, there are crucial side effects in the natural cells due to p53 induction caused by Mdm2 inhibition. Secondly, at the post-treatment stage, by the compositions, p53 activation leads to Mdm2 protein integration. Besides p53, p73, p63, E2F1, and HIF1a proteins are targeted by Mdm2 protein [53]. Mdm2 leads to XIAP integration and apoptosis inhibition [54]. … [55] Deacetylation of p53 in lysine-382 by SirT1 leads to p53 inactivation and instability. Therefore, SirT1 enzyme acts as a negative regulator of p53 and through its inhibition by special medications, it is possible to increase the activity of natural p53 [56, 57]. … [58] Tenovin-1 and Tenovin-6 are the most important SirT1/SirT2 inhibitors. In targeting natural p53 to inhibit it temporarily, the side effects should be reduced by p53 temporary inhibition in the natural cells during treatment of tumors with defective p53 [59]. PFT-α and PFT-μ are two classes of small molecules that inhibit transcription activity of p53 and its ability to connect to mitochondria. The groups can be used in the clinical utilization in composition with the drug-ray in cancer treatment [60]. In p53 reactivating, in targeting the mutant p53 to restore its activity, the utilization of the synthetic peptides or small molecules, which help proper spatial structure folding of p53 and include CDB3, CP-31398, PRIMA-1, MIRA-1, Ellipticine, WR-1065, and p53R3, is one of the main approaches to restore the mutant p53 activity [55, 61-73]. … [74, 75] In the targeting of the mutant p53 to kill the cells containing it, concerning p53, the utilization of the synthetic lethality to recognize the chemical compounds selectively carrying cancer cells with mutant p53 is very crucial in discovering a new class of anti-cancer medications (Fig. 3). Paclitaxel, Metformin, UCN01, and PD0166285 are some synthetic lethality medications of p53 [76-79]. … [80]

Non-declared

Non-declared

Non-declared

Regarding its important role to inhibit carcinogenesis, p53 is one of the main medication targets to heal cancers. Based on the type of genetic changes in p53 in healthy and cancer cells, a composition of different medications can be used. In addition, through better understanding of messaging paths with p53, new upstream or downstream proteins might be discovered, in order to act as targets for new medications.

Non-declared

Non-declared

Non-declared

Non-declared

TABLES and CHARTS

Show attach file


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