Prognostic Value of Multidrug Resistance 1, Glutathione-&lt;i&gt;S&lt;/i&gt;-Transferase-π and p53 in Advanced Nasopharyngeal Carcinoma Treated with Systemic Chemotherapy

Hsu, Chih‐Hung; Chen, Chi Long; Hong, Ruey‐Long; Chen, Kai Lii; Lin, Jing; Cheng, Ann‐Lii

doi:10.1159/000065061

Cited by 32 publications

(28 citation statements)

References 33 publications

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“…Doxorubicin is a DNA-damaging agent that is classically used to show TP53 inducibility (20,21). Doxorubicin-and cisplatin-based regimens have been used in the treatment of nasopharygeal carcinoma, and lack of TP53 staining has been associated with decreased response (8). As expected, TP53 mRNA levels in normal HEKA controls were significantly induced 6 h after doxorubicin treatment (Fig.…”

Section: Resultssupporting

confidence: 55%

“…We have recently shown increased activation of NF-nB phosphoSer 536 p65 and TP53 inactivation in the subset of HNSCC with wild-type TP53 (27,43) and have preliminary data indicating that quinacrine can inhibit NF-nB reporter activity and restore TP53 expression in cells found to underexpress TP53 in the same concentration range. 8 Activation of these transcription factors may be reciprocally related and contribute to cell survival in HNSCC. Thus, mechanisms involving inhibitory cross-talk, and effects of quinacrine on them, may also merit further investigation.…”

Section: Discussionmentioning

confidence: 99%

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Deficient TP53 Expression, Function, and Cisplatin Sensitivity Are Restored by Quinacrine in Head and Neck Cancer

Friedman

Nottingham

Duggal

et al. 2007

Clinical Cancer Research

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Purpose: To determine the nature and potential pharmacologic reversibility of deficient TP53 expression and function in head and neck squamous cell carcinomas (HNSCC) with wild-type TP53, previously associated with decreased sensitivity to cisplatin therapy. Experimental Design: TP53 genotype, mRNA and protein expression, TP53-induced p21 expression, and TP53 DNA^binding and reporter gene function were determined in a panel of nine previously characterized HNSCC cell lines from the University of Michigan squamous cell carcinoma (UM-SCC) series. The genotoxic drug doxorubicin and the anti-inflammatory and antimalarial drug quinacrine, previously identified as inducers of TP53, were used to examine the nature and potential reversibility of deficient TP53 expression and function. The specific role of inducibleTP53 on function and cellular proliferation was confirmed using selectiveTP53 inhibitor pifithrin-a or short hairpin RNA knockdown. The capability of quinacrine to sensitize HNSCC to the cytotoxic effects of cisplatin was assessed. Results: UM-SCC cell lines with wild-type TP53 genotype underexpressed TP53 mRNA and protein when compared with normal human keratinocytes or UM-SCC with mutant TP53. Although doxorubicin failed to induce TP53 expression or functional activity, quinacrine induced TP53 mRNA and protein expression, increased TP53 reporter activity and p21 protein expression, and induced growth inhibition in these wild-type TP53 cell lines. Quinacrineinduced TP53 reporter activity and growth suppression were attenuated by pifithrin-a and TP53 short hairpin RNA knockdown. Furthermore, quinacrine sensitized UM-SCC to cisplatin in vitro. Conclusions: Deficient TP53 mRNA and protein expression underlies decreased function in a subset of HNSCC with wild-type TP53 and can be restored together with cisplatin sensitization by quinacrine. TP53, a tumor suppressor gene important in regulating cellcycle arrest, apoptosis, and therapeutic sensitivity, represents one of the most common targets for alterations underlying the development of cancer, including head and neck squamous cell carcinomas (HNSCC; refs. 1 -5). Mutation of TP53 occurs in f40% to 50% of HNSCC, resulting in altered TP53 expression and function (3 -5). In HNSCC that retain wild-type TP53 genotype, approximately one half expressed detectable TP53 protein, whereas approximately one half exhibited deficient expression by immunohistochemistry (6). In the latter subset of HNSCC that retain wildtype TP53 genotype, the alterations resulting in a defect in TP53 expression or function have been shown to include protein inactivation after infection with human papilloma virus (HPV), defects of p16INK4a and other components of the DNA damage response pathway, or unknown mechanisms. As a consequence, the differing nature and effects of these multiple alterations on TP53 expression and function likely contributed to the frequent discordance of results between studies using immunohistochemistry, genotyping, or other methods to define the role of TP53 in...

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Section: Resultssupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Deficient TP53 Expression, Function, and Cisplatin Sensitivity Are Restored by Quinacrine in Head and Neck Cancer

Friedman

Nottingham

Duggal

et al. 2007

Clinical Cancer Research

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“…The biomarkers include circulating markers in the blood, such as Epstein -Barr virus (EBV) DNA (Chien et al, 2001) and CYFRA 21-1 (Ma et al, 2004), as well as tumour immunohistochemical markers such as the expression of multidrug-resistance protein (Hsu et al, 2002), epidermal growth factor receptors and signal transducers and activators of transcription factors (Hsiao et al, 2003). Among them, plasma EBV DNA has been the most validated and has been shown to be a predictor of poor survival after radiotherapy for local disease (Chan et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Validation of a new prognostic index score for disseminated nasopharyngeal carcinoma

Toh

Heng

et al. 2005

Br J Cancer

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Patients with metastatic nasopharyngeal carcinoma have variable survival outcomes. We previously designed a scoring system to better prognosticate these patients. Here, we report results on validation of this new prognostic index score in a separate cohort of patients. Clinical features and laboratory parameters were examined in 172 patients with univariate and multivariate analyses and a numerical score was derived for each independent prognostic variable. Significant independent prognostic variables and their scores assigned included poor performance status (score 5), haemoglobin o12 g dl À1 (score 4) and disease-free interval (DFI) (DFIp6 months (score 10) or metastases at initial diagnosis (score 1)). Maximum score was 19 and patients stratified into three prognostic groups: good, 0 -3; intermediate, 4 -8; poor, X9. When applied to a separate cohort of 120 patients, 59 patients were good, 43 intermediate and 18 poor prognosis, with median survivals of 19.6 (95% CI 16.1, 23.1), 14.3 (95% CI 12.3, 16.2) and 7.9 (95% CI 6.6, 9.2) months, respectively. (logrank test: P ¼ 0.003). We have validated a new prognostic score with factors readily available in the clinics. This simple score will prove useful as a method to prognosticate and stratify patients as well as to promote consistent reporting among clinical trials.

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“…Actin served as the internal control for loading. cells metastasize to distant organs (28,29), and there are limited drugs available for the prevention of cancer metastasis. The present study aimed to examine the potential application of berberine in the treatment of NPC, particularly in the prevention of metastatic spread, using a commonly used NPC cell line (HONE1).…”

Section: Discussionmentioning

confidence: 99%

Berberine inhibits Rho GTPases and cell migration at low doses but induces G2 arrest and apoptosis at high doses in human cancer cells

Tsang

Lau²,

Di³

et al. 2009

Int J Mol Med

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Abstract. Berberine is an active ingredient extracted fromCoptidis rhizoma which has been used for centuries as a traditional Chinese medicine for treatment of inflammatory diseases. Recent studies have indicated that berberine has anticancer properties. Berberine arrested cell growth and inhibited cell migration in various cancer cell lines. In this study, we examined the effects of berberine on HONE1 cells, which have been commonly used as a cell model for nasopharyngeal carcinoma. We observed the inhibitory effects of berberine on HONE1 cells at a high dosage (>150 μM). Berberine effectively induced the mitotic arrest of HONE1 cells at 300 μM which was associated with apoptosis. Berberine had differential intracellular localization at low and high doses. At a low dose (50 μM), berberine was localized in the mitochondria while at a high dose (300 μM), berberine was localized in the nucleus which may have induced mitotic arrest. Berberine effectively inhibited cell migration and invasion at low doses. Using a specific GST pull-down assay of activated Rho GTPases, we demonstrated that berberine suppressed the activation of Rho GTPases including RhoA, Cdc42 and Rac1. This indicates a novel function of berberine in the suppression of Rho GTPase signaling to mediate its inhibitory action on cell migration and motility. The potential of berberine to inhibit cancer metastasis in cancer warrants further investigation.

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Prognostic Value of Multidrug Resistance 1, Glutathione-<i>S</i>-Transferase-π and p53 in Advanced Nasopharyngeal Carcinoma Treated with Systemic Chemotherapy

Cited by 32 publications

References 33 publications

Deficient TP53 Expression, Function, and Cisplatin Sensitivity Are Restored by Quinacrine in Head and Neck Cancer

Deficient TP53 Expression, Function, and Cisplatin Sensitivity Are Restored by Quinacrine in Head and Neck Cancer

Validation of a new prognostic index score for disseminated nasopharyngeal carcinoma

Berberine inhibits Rho GTPases and cell migration at low doses but induces G2 arrest and apoptosis at high doses in human cancer cells

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