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  1. Targeting Mutant-p53 for Cancer Treatment: Are We There Yet?
    Lim DV, Woo WH, Lim JX, Loh XY, Soh HT, Lim SYA, et al.
    Curr Mol Pharmacol, 2024;17(1):e140923221042.
    PMID: 37711005 DOI: 10.2174/1874467217666230914090621
    BACKGROUND: Mutations in the TP53 gene are the most common among genetic alterations in human cancers, resulting in the formation of mutant p53 protein (mutp53). Mutp53 promotes proliferation, migration, invasion, and metastasis in cancer cells. Not only does the initiation of oncogenesis ensue due to mutp53, but resistance towards chemotherapy and radiotherapy in cancer cells also occurs. This review aims to summarise and discuss the oncogenesis of mutant p53 in cancer cells and introduce the various mutant p53 inhibitors currently being evaluated at the pre-clinical and clinical stages. Compounds that induce the wild-type conformation on the targeted p53 missense mutation, restore or enhance the DNA binding of mutant p53, and inhibit cancer cells' growth are highlighted. In addition, the progression and development of the mutant p53 inhibitors in clinical trials are updated.

    CONCLUSION: The progress of developing a cancer treatment that may successfully and efficiently target mutant p53 is on the verge of development. Mutant p53 proteins not only initiate oncogenesis but also cause resistance in cancer cells to certain chemo or radiotherapies, further endorse cancer cell survival and promote migration as well as metastasis of cancerous cells. With this regard, many mutant p53 inhibitors have been developed, some of which are currently being evaluated at the pre-clinical level and have been identified and discussed. To date, APR-246 is the most prominent one that has progressed to the Phase III clinical trial.

    Matched MeSH terms: Genes, p53*
  2. Fulltext Mutations of the p53 gene in gliomas from Malay patients
    Jafri A, Aziz MY, Ros S, Nizam I
    Med J Malaysia, 2003 Jun;58(2):236-42.
    PMID: 14569744
    This is the first investigation performed to detect the presence of the p53 mutation in Malay patients with gliomas. The p53 gene was amplified using polymerase chain reaction (PCR) from 33 fresh-frozen tumour tissues from patients histologically confirmed as glioma. Four hot spot areas that lie between exon 5 to 8 were screened for mutation by mean of non-isotopic "cold" single strand conformation polymorphism (SSCP) analysis and direct sequencing. The frequency of p53 gene mutation in gliomas examined was 33% (11 of 33). Five (45.5%) cases had mutation in exon 7, four (36.4%) had mutation in exon 8 and two (18.1%) had mutation in exon 6. Seven (63.6%) of 11 mutations were single nucleotide point mutations of which 5 were missense mutations, 1 was nonsense mutation and 1 was, silent mutation. Three (27.3%) showed insertion mutation and 1 (9.1%) showed deletion mutation. Of the point mutations, 57.1% were transitions and 42.9% were transversions. These results suggested that p53 mutations frequently occur in gliomas and this gene does play an important role in the tumourigenesis process of Malay patients with brain tumours.
    Matched MeSH terms: Genes, p53/genetics*
  3. Fulltext Quantitative analysis of the expression of p53 gene in colorectal carcinoma by using real-time PCR
    Bong I, Lim P, Balraj P, Sim Ui Hang E, Zakaria Z
    Trop Biomed, 2006 Jun;23(1):53-9.
    PMID: 17041552 MyJurnal
    Colorectal carcinoma ranks third among ten leading causes of cancer in Malaysia. The colorectal carcinoma tumourigenesis involves the inactivation of tumour suppressor genes, and activation of proto-oncogenes. The p53 is one of the tumour suppressor genes that is involved in the colorectal carcinogenesis. The p53 gene is located on human chromosome 17p13.1 and comprises of 11 exons. Deficiencies in the p53 gene can cause the cancerous cells to spread to distant organs such as liver, lungs, lymph nodes, spine and bone. The most common p53 abnormalities that can lead to the metastasis of colorectal tumours are mutation and deregulation of the gene. In this study, nine colorectal carcinoma samples were used to establish a simple and sensitive strategy in the study on in vivo p53 expression by using realtime LightCycler SYBR Green I technology.
    Matched MeSH terms: Genes, p53*
  4. Fulltext Primary Axillary Vein Leiomyosarcoma in Li-Fraumeni Syndrome
    Roslly MZ, Omar N, Naim MS
    Radiol Imaging Cancer, 2024 Jan;6(1):e230184.
    PMID: 38276907 DOI: 10.1148/rycan.230184
    Matched MeSH terms: Genes, p53
  5. Fulltext p53: an overview of over two decades of study
    Cheah PL, Looi LM
    Malays J Pathol, 2001 Jun;23(1):9-16.
    PMID: 16329542
    p53 is the most commonly mutated gene in human cancers. It encodes a 53 kilodalton protein with several evolutionarily conserved domains viz sequence-specific DNA binding, tetramerisation, SH3 molecule binding, C-terminal and N-terminal. Existing in the cell at a very low level and in a relatively inactive form, p53 protein is increased and activated during periods of cellular stress. Unlike other proteins, the increase in protein level and its activation result from modification of the protein rather than genetic transcriptional or translational upregulation. Normally, Mdm2 protein interacts with p53 protein and effectively targets it for ubiquitin proteolysis within an autoregulatory feedback loop. Phosphorylation at the N-terminus reduces p53 interaction with Mdm2 with a resultant increase in p53 protein level. Modification at the C and N termini via phosphorylation or acetylation upregulates binding to specific DNA targets increasing transcription of these downstream genes. The net effect of p53 protein increase and activation lies in arrest of the cell in cycle which allows time for repair of the incurred damage or apoptosis or death of the cell. Failure of these normal protective and adaptive mechanisms caused by mutation of the p53 gene with product of an abnormal protein, loss of p53 protein through interaction with and degradation by HPV E6 protein or overexpressed Mdm2 etc. permits DNA-damaged cells to continue replicating. Left unchecked, this frequently contributes to tumourigenesis. Various methods have been devised to screen for mutations of the p53 gene, still the most common source of failed p53 mechanism. These include immunohistochemical detection of mutated proteins or identification of altered electrophoretic mobility of mutated p53 sequences. Sequencing of the gene nonetheless remains the most accurate method for determination of mutation. Major advances have been made in p53 research but the most meaningful probably lies in the promising results achieved in tumour therapy where introduction of wild type p53 gene has resulted in regression of non-small-cell lung cancer (NSCLC). Many other notable developments in this field include description of p53 homologues, "gain of function" mutants, p53 polymorphisms, angiogenesis-inhibiting properties of wild type p53 protein etc.
    Matched MeSH terms: Genes, p53*
  6. Frequent occurrence of gastric cancer in Asian kindreds with Li-Fraumeni syndrome
    Ariffin H, Chan AS, Oh L, Abd-Ghafar S, Ong GB, Mohamed M, et al.
    Clin Genet, 2015 Nov;88(5):450-5.
    PMID: 25318593 DOI: 10.1111/cge.12525
    Type of cancer and age of onset in individuals with inherited aberrations in the tumour suppressor gene TP53 are variable, possibly influenced by genetic modifiers and different environmental exposure. Since 2009, the modified Chompret criteria (MCC) have been used to identify individuals for TP53 mutation screening. Using the TP53 mutation database maintained by the International Agency for Research on Cancer (IARC), we investigated if the MCC, mainly developed for a Caucasian population, was also applicable in Asia. We identified several differences in Asian families compared with similar Caucasian cohorts, suggesting that identification and management of Li-Fraumeni syndrome in Asia do not completely mirror that of North America and Western Europe. Early gastric cancer (<40 years) may be considered a new addition to the MCC especially for Asian families.
    Matched MeSH terms: Genes, p53
  7. Novel MDM2 splice variants identified from oral squamous cell carcinoma
    Sam KK, Gan CP, Yee PS, Chong CE, Lim KP, Karen-Ng LP, et al.
    Oral Oncol, 2012 Nov;48(11):1128-35.
    PMID: 22705356 DOI: 10.1016/j.oraloncology.2012.05.016
    The presence of a variety of MDM2 splice variants has been reported in a range of different tumor types and is associated with poor patient prognosis. Furthermore, several MDM2 variants have been shown to have oncogenic properties. Despite this, MDM2 splice variants have not been comprehensively characterized in oral squamous cell carcinoma (OSCC).
    Matched MeSH terms: Genes, p53/genetics
  8. Fulltext Association of Arg72Pro of P53 polymorphism with colorectal cancer susceptibility risk in Malaysian population
    Aizat AA, Shahpudin SN, Mustapha MA, Zakaria Z, Sidek AS, Abu Hassan MR, et al.
    Asian Pac J Cancer Prev, 2011;12(11):2909-13.
    PMID: 22393962
    BACKGROUND: Colorectal cancer (CRC) results from the interaction between environmental exposures and genetic predisposition factors.

    AIMS: A case control study was designed and to investigate the genotype frequencies of P53Arg72Pro polymorphism in Malaysian CRC patients and healthy controls and to determine the associated risk of this polymorphism with CRC predisposition.

    METHODS: In this case-control study, peripheral blood samples of 202 sporadic CRC patients and 201 normal controls were collected, DNA extracted and genotyped using the polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) technique.

    RESULTS: Genotype analysis showed the frequency of homozygous variant (Pro/Pro) genotype (21%) to be significantly higher in cases compared to controls (13%), (p=0.013). On examining the association between variant genotypes and CRC risk, the Pro/Pro homozygous variant genotype showed significantly higher risk association with CRC susceptibility (OR: 2.047, CI: 1.063-4.044, p=0.033). When stratified according to age, we observed that, individuals aged above 50 years and carriers of pro/pro genotype had significantly higher risk with OR: 3.642, CI: 1.166-11.378, p=0.026.

    CONCLUSIONS: Our results suggest that the codon 72 SNP which results in amino acid substitution of Arginine to Proline in cell cycle regulatory gene P53, is associated with sporadic CRC risk and carriers of Pro/Pro genotype and more than 50 years old may have high susceptibility.
    Matched MeSH terms: Genes, p53*
  9. Immunohistochemical expression of p53 proteins in Wilms' tumour: a possible association with the histological prognostic parameter of anaplasia
    Cheah PL, Looi LM, Chan LL
    Histopathology, 1996 Jan;28(1):49-54.
    PMID: 8838120
    Wilms' tumour (nephroblastoma) has been associated with chromosomal abnormalities at the 11p13, 11p15 and 16q regions. A study into the possibility of mutations occurring within p53, the ubiquitous adult tumour suppressor gene, in Wilms' tumour was carried out. Thirty-eight cases were studied. Of these 36 were categorised into the favourable histology group and two into the unfavourable histology group based on the National Wilms' Tumour Study criteria. Archival formalin-fixed, paraffin-embedded tissue sections from each case were stained with a polyclonal (AB565:Chemicon) and a monoclonal (DO7:Dako) antibody raised against p53 protein using a peroxidase-labelled streptavidin biotin kit (Dako). 'Cure' (disease-free survival of 60 months or longer) was documented in 39% of cases with favourable histology tumours. Eleven percent in this group succumbed to the disease. Both cases with unfavourable histology died. Four out of 36 (11%) tumours with favourable histology demonstrated weak to moderate staining with both AB565 and DO7 in more than 75% of tumour cells. In contrast, p53 protein expression in unfavourable histology tumours was significantly increased compared with the favourable histology group (P = 0.021) with both cases demonstrating immunopositivity in > 75% of tumour cells when stained with AB565 and DO7. The intensity of staining ranged from moderate to strong in both cases. It appears from this preliminary study that the immunohistochemical expression of p53 protein in Wilms' tumour, presumably a result of mutation in the p53 tumour suppressor gene, correlates with histological classification, histological categorisation being one of the useful features in the prognostic assessment of Wilms' tumours.
    Matched MeSH terms: Genes, p53/genetics
  10. p53 codon 72 polymorphisms and random amplified polymorphic DNA analysis of non-melanoma skin cancer through archival formalin-fixed paraffin-embedded tissue
    Yoke-Kqueen C, Ab Mutalib NS, Sidik SM, Learn-Han L, Geok-Chin T
    Oncol Rep, 2012 Mar;27(3):753-63.
    PMID: 22159872 DOI: 10.3892/or.2011.1581
    Non-melanoma skin cancer (NMSC) is classified among the ten most frequent cancers in Malaysia. A common polymorphism at codon 72 of the p53 tumor suppressor gene and its influence on cancer risk has been studied for different types of cancer with mixed and inconsistent results with limited published data on the Malaysian population so far. In the present study, the frequency of p53 codon 72 polymorphism in 60 patients with NMSC was investigated from archival formalin-fixed paraffin-embedded (FFPE) tissue obtained from Hospital Universiti Kebangsaan Malaysia (HUKM). Additionally, random amplified polymorhic DNA -polymorphic chain reaction (RAPD-PCR) was employed for preliminary biomarker development. NMSC FFPE samples (70%) possess Arg/Arg, 20% with Pro/Pro and 10% with Arg/Pro. In total, there was no significant difference in the p53 codon 72 genotypes between histological types of NMSC, gender, race, tumor location and age group. However, there was an apparent age-associated increase in the Arg/Arg genotype but did not reach statistical significance (P=0.235). NMSC types and demographic characteristics did not influence genotype distribution. On the other hand, BCC and SCC distributions are influenced by age group, race and tumor location.
    Matched MeSH terms: Genes, p53*
  11. Fulltext Recurrent paediatric supratentorial extraventricular ependymoma associated with genetic mutation at exon 4 of p53 gene
    Ghani AR, Abdullah JM, Ghazali M, Ahmad F, Ahmad KA, Madhavan M
    Singapore Med J, 2008 Jul;49(7):e192-4.
    PMID: 18695856
    Recurrent supratentorial extraventricular ependymoma in a four-year-old Malay boy treated twice surgically in combination with cranial radiotherapy is reported. He presented with symptoms of raised intracranial pressure and a history of focal seizure. Computed tomography of the brain showed a left supratentorial extraventricular cystic lesion causing a mass effect. The tumour histology was ependymoma (WHO grade II). The clinical course, radiological characteristics and management of this tumour are discussed. Molecular genetic analysis of p53 and p27 genes revealed substitution of nucleotide G to C at location nucleotide 12139, exon 4 of gene p53. No alteration was detected at exon 5-6 and 8 of p53 gene and exon 1 and 2 of p27 gene.
    Matched MeSH terms: Genes, p53*
  12. Higher frequency of p53 gene mutations in diffuse large B-cell lymphoma with MALT component
    Tai YC, Tan JA, Peh SC
    Pathol. Int., 2004 Nov;54(11):811-8.
    PMID: 15533223
    p53 gene mutation is not a frequent event in the tumorigenesis of lymphomas and the expression of p53 protein is independent of p53 gene mutations. The present study aimed to investigate mutations in the p53 gene in a series of extranodal B-cell lymphomas, and its association with p53 protein expression. A total of 52 cases were graded histologically into Grade 1, Grade 2 and Grade 3 tumors and p53 protein expression was detected using immunohistochemistry. Mutations in the p53 gene were analyzed using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) and mobility shifts were confirmed by direct sequencing. The tumors comprised 26 (50%) Grade 1, 9 (17%) Grade 2 and 15 (29%) Grade 3. A high proportion of Grade 2 (25%) tumors expressed p53 protein (P = 0.051) and carried p53 gene mutation (33%) (P = 0.218). However, p53 protein expression was not associated with p53 gene mutations (P = 0.057). Transversion mutations (88%) were more frequently detected than transition mutations (12%). The present study revealed that p53 gene mutations and p53 protein expression occurred in higher frequencies in Grade 2 tumors, which may be of pathogenetic importance. The high frequency of transversion mutations may reflect the influence of an etiological agent in the tumorigenesis of mucosa-associated lymphoid tissue (MALT lymphoma).
    Matched MeSH terms: Genes, p53/genetics*
  13. Fulltext ER, p53 and MIB-1 are significantly associated with malignant phyllodes tumor
    Munawer NH, Md Zin R, Md Ali SA, Muhammad R, Ali J, Das S
    Biomed J, 2012 Nov-Dec;35(6):486-92.
    PMID: 23442362 DOI: 10.4103/2319-4170.104414
    Fibroadenomas (FA) are common while phyllodes tumors (PT) are rare and both tumors are composed of epithelial and stromal components. We evaluated the expression status of ER, Bc12, p53, and MIB-1 protein in these tumors.
    Matched MeSH terms: Genes, p53/physiology*
  14. Fulltext Immunohistochemical Study of p53 Expression in Premalignant and Malignant Cervical Neoplasms
    Tan, GC, Sharifah, N.A., Salwati, S., Hatta, A.Z., Shiran, M.S, Ng, Ho
    Medicine & Health, 2007;2(2):125-132.
    MyJurnal
    One of the most important cervical cancer risk factors is human papillomavirus (HPV) infection. The p53 gene is one of the most important targets of the HPV E6 gene. E6 protein has the ability to stimulate p53 degradation, inhibits several functions of wild-type p53 and it competes with its function including suppression of malignant growth. The aim of this study is to determine the differences in p53 expressions in pre-malignant and malignant cervical neoplasms. This is a retrospective study on 100 cases of cervical neoplasms. There were 21 cases of CIN 1, 8 cases of CIN 2, 25 cases of CIN 3, 36 cases of squamous cell carcinoma, 7 cases of adenocarcinoma and 3 cases of adenosquamouscarcinoma. All cases were evaluated by immunohistochemistry using p53 monoclonalantibody. Thirty six of the 54 pre-malignant cases (66.7%) were positive for p53 protein, n contrast to the malignant cases in which, 40 of the 46 cases (87.0%) were positive. he majority of CIN showed absent to focal staining (29/54, 53.7%). In contrast, 84.8% (39/46( of the invasive carcinoma showed regional to diffuse staining. The expression of p53 is greater in the malignant cervical neoplasms than the pre-malignant cervical lesions, suggesting that p53 overexpression is not an early phenomenon in the pathogenesis of cervical cancer. It is also shown to be slightly higher in percentage in CIN 2 and 3 when compared with CIN 1. However, a number of cases were p53 negative, suggesting that other factors may be involved and further HPV studies are indicated.
    Matched MeSH terms: Genes, p53
  15. Fulltext Effect of perivitelline fluid from horseshoe crab on the expression of cell cycle regulatory genes in human dental pulp stem cells
    Abdul Qawee Rani, Thirumulu Ponnuraj Kannan, Nur Izyan Azmi, Najian Binti Ibrahim, Nor Shamsuria Omar, Ahmad Azlina, et al.
    Archives of Orofacial Sciences, 2016;11(1):7-14.
    MyJurnal
    Perivitelline fluid (PVF) of the horseshoe crab embryo has been reported to possess an important role
    during embryogenesis by promoting cell proliferation. This study aims to evaluate the effect of PVF on the
    expression of cell cycle regulatory genes from human dental pulp stem cells (DPSCs) between different cell
    passages viz. 4, 5, 6. The cells were treated with a single dose of PVF (26.89 mg/ml) PVF. Gene expression was
    quantified for CDKNA2A, PTEN, MDM2 and TP53 genes using reverse transcriptase PCR. CDKN2A and MDM2
    expression for treated and untreated DPSCs, expressed a similar pattern of expression. The higher expression of
    CDKN2A showed that the treatment increased cell proliferation and prevented cell senescence. DPSCs with PVF
    treatment showed increased expression of MDM2 at passage 4 and drastically declined expression at passage 5
    and slightly increased at passage 6. TP53 expression of DPSCs treated group showed a higher expression
    compared to untreated group. On the other hand, the expression of PTEN in DPSCs treated group started to
    increase from passage 5 to 6. However, on the whole, the PTEN expression was higher than the untreated group
    in all the passages studied here. The results showed that PVF could enhance cell cycle regulatory gene
    expression in DPSCs as indicated by the higher expression of all the genes considered in this study at different
    cell passages in the treated group compared to the untreated group. Mann Whitney test was utilized to determine
    the significance of cell cycle regulatory genes expression between treated and untreated group. Significant
    difference in expression of genes between the treated and untreated groups were found at all passages except
    for CDKN2A gene whereby, its expression was not significantly different at passage 5 though it did express
    slightly higher in PVF treated DPSCs.
    Matched MeSH terms: Genes, p53
  16. A gain of function p53 gene mutant promotes growth suppression in human liver cancer cells
    Nor Adzimah Johdi, Siti Nurmi Nasir, Rahman Jamal
    Sains Malaysiana, 2017;46:1289-1297.
    Primary liver cancer is one of the most common cancer in the world with highest cancer mortality rate. The most common type of primary liver cancer is hepatocellular carcinoma (HCC). There are many risk factors for liver cancer and currently available treatments for HCC are largely inadequate. Gene mutation and dysfunction of p53 are common and is recognized as an important molecular event in hepatocarcinogenesis. Therefore, replacement of the aberrant p53 gene is an attractive approach in the treatment of HCC providing an alternative treatment for primary HCC. In this study, we assessed whether the transfection with wild-type p53 gene is able to restore the pro-apoptotic effects and evaluate the feasibility of gene therapy in fixing a faulty p53 molecule. We established a non-viral cationic lipid-based p53 gene delivery into two human HCC cell lines namely HLF and PLC/PRF/5 cells. Both cell lines have mutations in the p53 gene. We compared the results with the normal liver cell line, WRL68, that constitutively expresses the wild-type p53 gene. In this study, the introduction of wild-type p53 gene into HLF and PLC/PRF/5 cells resulted in an increased of p53 gene expression, protein expression and cells growth inhibition shown in MTS reduction cell viability assay, FITC-Annexin V and PI apoptosis assay, western blot and caspase activity assay. In summary, the study provides a promising therapeutic approach for p53 gene delivery into HCC patients. The p53 gene delivery can be instituted together with chemotherapy as a combination treatment to induce apoptosis.
    Matched MeSH terms: Genes, p53
  17. Polymorphisms of cell cycle regulator genes CCND1 G870A and TP53 C215G: Association with colorectal cancer susceptibility risk in a Malaysian population
    Zahary MN, Ahmad Aizat AA, Kaur G, Yeong Yeh L, Mazuwin M, Ankathil R
    Oncol Lett, 2015 Nov;10(5):3216-3222.
    PMID: 26722315
    Colorectal cancer (CRC) occurs as a more common sporadic form and a less common familial form. Our earlier analysis of germline mutations of mismatch repair genes confirmed only 32% of familial CRC cases as Lynch syndrome cases. It was hypothesized that the remaining familial aggregation may be 'polygenic' due to single nucleotide polymorphisms (SNPs) of low penetrance genes involved in cancer predisposition pathways, such as cell cycle regulation and apoptosis pathways. The current case-control study involving 104 CRC patients (52 sporadic and 52 familial) and 104 normal healthy controls investigated the contribution of the SNPs cyclin D1 (CCND1) G870A and tumor protein p53 (TP53) C215G in modulating familial and sporadic CRC susceptibility risk. DNA was extracted from peripheral blood and the polymorphisms were genotyped by employing a polymerase chain reaction-restriction fragment length polymorphism method. The association between these polymorphisms and CRC susceptibility risk was calculated using a binary logistic regression analysis and deriving odds ratios (ORs). The A/A variant genotype of CCND1 and G/G variant genotype of TP53 exhibited a significantly greater association with the risk of sporadic CRC [CCND1: OR, 3.471; 95% confidence interval (CI), 1.443-8.350; P=0.005. TP53: OR, 2.829; CI, 1.119-7.152; P=0.026] as well as familial CRC susceptibility (CCND1: OR, 3.086; CI, 1.270-7.497; P=0.019. TP53: OR, 3.048; CI, 1.147-8.097; P=0.030). The results suggest a potential role of the SNPs CCND1 G870A and TP53 C215G in the modulation of sporadic and familial CRC susceptibility risk.
    Matched MeSH terms: Genes, p53
  18. Chlorella vulgaris modulates the expression of senescence-associated genes in replicative senescence of human diploid fibroblasts
    Jaafar F, Durani LW, Makpol S
    Mol Biol Rep, 2020 Jan;47(1):369-379.
    PMID: 31642042 DOI: 10.1007/s11033-019-05140-8
    Human diploid fibroblasts (HDFs) cultured in vitro have limited capacity to proliferate after population doubling is repeated several times, and they enter into a state known as replicative senescence or cellular senescence. This study aimed to investigate the effect of Chlorella vulgaris on the replicative senescence of HDFs by determining the expression of senescence-associated genes. Young and senescent HDFs were divided into untreated control and C. vulgaris-treated groups. A senescence-associated gene transcription analysis was carried out with qRT-PCR. Treatment of young HDFs with C. vulgaris reduced the expression of SOD1, CAT and CCS (p 
    Matched MeSH terms: Genes, p53/genetics
  19. Li-Fraumeni syndrome in a Malaysian kindred
    Ariffin H, Martel-Planche G, Daud SS, Ibrahim K, Hainaut P
    Cancer Genet. Cytogenet., 2008 Oct;186(1):49-53.
    PMID: 18786442 DOI: 10.1016/j.cancergencyto.2008.06.004
    We report on a Malaysian kindred with Li-Fraumeni syndrome. The proband was an 8-year-old girl who presented with embryonal rhabdomyosarcoma of the trunk at the age of 8 months and developed a brain recurrence at the age of 7 years, which was 5 years after remission. A younger sister later developed adrenocortical carcinoma at the age of 6 months. Their mother and maternal grandmother were diagnosed with breast cancer at the ages of 26 and 38 years, respectively. TP53 mutation detection in this family revealed a duplication of a GGCGTG motif starting at nucleotide 17579 in exon 10, resulting in an in-frame insertion of two amino acids between residues 334 and 336 in the tetramerization domain of the p53 protein. This mutation was found in the proband and her affected sister as well as her mother. In addition, the mutation was detected in two other siblings (a brother aged 3 years and a sister aged 18 months) who have not yet developed any malignancy. Sequencing of TP53 in the father and two other asymptomatic siblings revealed wild-type TP53. To our knowledge, this is a first report of a Li-Fraumeni syndrome family in Southeast Asia.
    Matched MeSH terms: Genes, p53
  20. Molecular mechanisms of apoptosis and cell selectivity of zinc dithiocarbamates functionalized with hydroxyethyl substituents
    Tan YS, Ooi KK, Ang KP, Akim AM, Cheah YK, Halim SN, et al.
    J Inorg Biochem, 2015 Sep;150:48-62.
    PMID: 26086852 DOI: 10.1016/j.jinorgbio.2015.06.009
    In the solid state each of three binuclear zinc dithiocarbamates bearing hydroxyethyl groups, {Zn[S2CN(R)CH2CH2OH]2}2 for R = iPr (1), CH2CH2OH (2), and Me (3), and an all alkyl species, [Zn(S2CNEt2)2]2 (4), features a centrosymmetric {ZnSCS}2 core with a step topology; both 1 and 3 were isolated as monohydrates. All compounds were broadly cytotoxic, specifically against human cancer cell lines compared with normal cells, with greater potency than cisplatin. Notably, some selectivity were indicated with 2 being the most potent against human ovarian carcinoma cells (cisA2780), and 4 being more cytotoxic toward multidrug resistant human breast carcinoma cells (MCF-7R), human colon adenocarcinoma cells (HT-29), and human lung adenocarcinoma epithelial cells (A549). Based on human apoptosis PCR-array analysis, caspase activities, DNA fragmentation, cell apoptotic assays, intracellular reactive oxygen species (ROS) measurements and human topoisomerase I inhibition, induction of apoptosis in HT-29 cells is demonstrated via both extrinsic and intrinsic pathways. Compounds 2-4 activate the p53 gene while 1 activates both p53 and p73. Cell cycle arrest at the S and G2/M phases correlates with inhibition of HT-29 cell growth. Cell invasion is also inhibited by 1-4 which is correlated with down-regulation of NF-κB.
    Matched MeSH terms: Genes, p53
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