p53 as a target for the treatment of cancer

Duffy, Michael J.; Synnott, Naoise C; McGowan, Patricia M.; Crown, John; O’Connor, Darran P.; Gallagher, William M.

doi:10.1016/j.ctrv.2014.10.004

Cited by 202 publications

(162 citation statements)

References 92 publications

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“…In addition to the role as a tumor suppressor, p53 is also thought to be involved in cellular senescence and cell cycle arrest. p53 gene is located at the short arm of chromosome 17 (17p13.1) [4,14]. Under stable conditions, the p53 protein is controlled at low cellular level by the proteasome degradation pathway.…”

Section: Discussionmentioning

confidence: 99%

Expression of Interactive Genes Associated with Apoptosis and Their Prognostic Value for Ovarian Serous Adenocarcinoma

et al. 2016

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Section: Discussionmentioning

confidence: 99%

Expression of Interactive Genes Associated with Apoptosis and Their Prognostic Value for Ovarian Serous Adenocarcinoma

et al. 2016

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“…TNBCs represent ~15% of all breast cancer cases and are often accompanied by a higher frequency of p53 gene mutations (2,3). The tumor suppressor gene p53 serves a critical role in conferring cancer cell sensitivity to DNA-damaging agents (3).…”

Section: Introductionmentioning

confidence: 99%

“…The tumor suppressor gene p53 serves a critical role in conferring cancer cell sensitivity to DNA-damaging agents (3). Failure of p53 signaling leads to resistance to chemotherapeutics (3)(4)(5). p73 is a member of the p53 gene family.…”

Section: Introductionmentioning

confidence: 99%

Curcumol triggers apoptosis of p53 mutant triple-negative human breast cancer MDA-MB 231 cells via activation of p73 and PUMA

Huang

Liao

et al. 2017

Oncology Letters

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Abstract. Triple-negative breast cancer (TNBC; estrogen receptor-negative, progesterone receptor-negative and Her-2-negative) is often accompanied by a higher frequency of p53 gene mutations. Therefore, TNBC is challenging to treat due to a lack of biological targets and a poor sensitivity to conventional therapies. Curcumol is a monomer composition isolated from the ethanol extracts of Curcuma wenyujin, a Chinese medicinal herb traditionally used as a cancer remedy. Previous studies have revealed that curcumol is able to block proliferation in various human tumor cell lines. However, the underlying mechanisms have yet to be elucidated. The present study aimed to investigate the anticancer effects of curcumol in the human p53 mutant TNBC MDA-MB-231 cell line and its underlying mechanisms. Cell viability and growth were determined by MTT and a mice xenograft model assay, respectively. Cell cycle distribution was examined by flow cytometry. Apoptosis was evaluated by apoptotic morphology analysis with DAPI staining and flow cytometric analysis following Annexin V/propidium iodide staining. The protein expression in cells was eva luated by immunoblotting. Treatment of MDA-MB-231 cells with curcumol resulted in a significant inhibition of cell proliferation in vitro [half maximal inhibitory concentration (IC 50 )=240.7±85.0 µg/ml for 48 h and IC 50 =100.2±13.5 µg/ml for 72 h]. Curcumol treatment also resulted in the suppression of xenograft growth in vivo (100 or 200 µg/kg for 21 days), as well as G 1 phase arrest and an apoptotic response, which were accompanied by the upregulation of p73 expression and the activation of the expression of p53 upregulated modulator of apoptosis (PUMA) and Bcl-2 antagonistic killer (Bak). No cleavage of poly (ADP-ribose) polymerase was detected. To the best of our knowledge, the present data demonstrate for the first time that curcumol inhibits the growth of MDA-MB-231 cells and triggers p53-independent apoptosis, which may be media ted by the p73-PUMA/Bak signaling pathway. Curcumol may, therefore, be a potential compound for use in the development of novel TNBC therapeutics. IntroductionTriple-negative breast cancer (TNBC; estrogen receptor-negative, progesterone receptor-negative and Her-2-negative) remains challenging to treat due to the innate aggressive biological characteristics and the lack of effective therapies (1,2). TNBCs represent ~15% of all breast cancer cases and are often accompanied by a higher frequency of p53 gene mutations (2,3). The tumor suppressor gene p53 serves a critical role in conferring cancer cell sensitivity to DNA-damaging agents (3). Failure of p53 signaling leads to resistance to chemotherapeutics (3-5). p73 is a member of the p53 gene family. Under certain conditions, p73 is able to replace the p53 function in response to DNA damage, activate the transcription of p53-responsive genes and inhibit cell growth in a p53-like manner by inducing cell cycle arrest and apoptosis (6-8). Therefore, the identification of anticancer drugs able to activate p73 ...

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“…Therapeutically this link could be important as currently anti-p53 therapies [23] are in stages of development. Addition of these to anti-Her2-neu drugs such as traztuzumab might improve patients’ clinical outcome that has been so poor till now.…”

Section: Discussionmentioning

confidence: 99%

Incorporation of p-53 mutation status and Ki-67 proliferating index in classifying Her2-neu positive gastric adenocarcinoma

Ahmed

Al-Tamimi

2018

Libyan Journal of Medicine

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Her2-neu overexpression has a pathogenetic, therapeutic and a controversial prognostic role in gastric cancer. p-53 mutation status and Ki-67 proliferation index are established prognostic markers in many tumors. In this study we evaluated p-53 and Ki-67 in relation to Her2-neu positive and negative gastric adenocarcinoma (GA). This cross-sectional study was carried out at King Fahd Hospital of Imam Abdulrahman bin Faisal University. Fifty cases of GA were retrieved from pathology archives. Clinico-pathological parameters were evaluated. Immunohistochemical protein analysis for Her2-neu, Ki-67 and p-53 was carried out. Fluorescent in situ hybridization (FISH) analysis was done for Her2-neu positive cases showing 2+ immunoexpression. Frequency of Ki-67 and p-53 positivity in Her2-neu positive cases was calculated and compared with those in Her2-neu negative cases. Correlation of clinicopatological parameters with Her2 positive and negative cases, p-53 mutation status and Ki-67 proliferation index was carried out. Her2-neu overexpression was present in 12% (n = 6) cases. A high Ki-67 was seen predominantly in Her2-neu positive cases (83%, n = 5). Her2-neu negative cases (n = 44) showed moderate (31.88%, n = 14) to low (34%, n = 15) Ki-67. Diffuse p-53 positivity was seen predominantly in Her2-neu positive cases (33.33%, n = 2). Focal p-53 was seen mainly in Her2-neu negative cases 56.8% (n = 25). Negative p-53 was seen to be independent of Her2-neu status. Her2-neu positivity is strongly associated with diffuse p-53 mutation status and high Ki-67 proliferation. Her 2-neu negative status is associated with focal p-53 positivity and low to moderate Ki-67 proliferation index. Such stratifications in prognostic markers could not only be predictive in patient’s prognostics but could also form a basis of molecular classification of gastric cancer.

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p53 as a target for the treatment of cancer

Cited by 202 publications

References 92 publications

Expression of Interactive Genes Associated with Apoptosis and Their Prognostic Value for Ovarian Serous Adenocarcinoma

Expression of Interactive Genes Associated with Apoptosis and Their Prognostic Value for Ovarian Serous Adenocarcinoma

Curcumol triggers apoptosis of p53 mutant triple-negative human breast cancer MDA-MB 231 cells via activation of p73 and PUMA

Incorporation of p-53 mutation status and Ki-67 proliferating index in classifying Her2-neu positive gastric adenocarcinoma

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