Modulation of Cellular Response to Cisplatin by a Novel Inhibitor of DNA Polymerase β

Boudsocq, François; Benaim, Pierre; Canitrot, Yvan; Knibiehler, Martine; Ausseil, Frédéric; Capp, Jean‐Pascal; Bieth, Anne; Long, Christophe; David, Bruno; Shevelev, I. A.; Frierich-Heinecken, Erika; Hübscher, Ulrich; Amalríc, François; Massiot, Georges; Hoffmann, Jean-Sébastien; Cazaux, Christophe

doi:10.1124/mol.104.001776

Cited by 51 publications

(43 citation statements)

References 40 publications

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“…However, the result is unsatisfactory due to the acquisition of chemoresistance by tumor cells. Multiple mechanisms for chemoresistance have been described in various cancer cells (25)(26)(27). Chemotherapeutic compounds that induce apoptosis are also known to activate nuclear factor-nB (NF-nB) in the protection of genotoxic stress.…”

Section: Introductionmentioning

confidence: 99%

Lupeol Suppresses Cisplatin-Induced Nuclear Factor-κB Activation in Head and Neck Squamous Cell Carcinoma and Inhibits Local Invasion and Nodal Metastasis in an Orthotopic Nude Mouse Model

Lee¹,

Poon²,

Wo³

et al. 2007

Cancer Research

114

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A poor prognosis in head and neck squamous cell carcinoma (HNSCC) patients is commonly associated with the presence of regional metastasis. Cisplatin-based chemotherapy concurrent with radiation therapy is commonly used in the treatment of locally advanced HNSCC. However, the result is dismal due to common acquisition of chemoresistance and radioresistance. Epidemiologic studies have shown the importance of dietary substances in the prevention of HNSCC. Here, we found that lupeol, a triterpene found in fruits and vegetables, selectively induced substantial HNSCC cell death but exhibited only a minimal effect on a normal tongue fibroblast cell line in vitro. Down-regulation of NF-KB was identified as the major mechanism of the anticancer properties of lupeol against HNSCC. Lupeol alone was not only found to suppress tumor growth but also to impair HNSCC cell invasion by reversal of the NF-KB-dependent epithelial-to-mesenchymal transition. Lupeol exerted a synergistic effect with cisplatin, resulting in chemosensitization of HNSCC cell lines with high NF-KB activity in vitro. In in vivo studies, using an orthotopic metastatic nude mouse model of oral tongue squamous cell carcinoma, lupeol at a dose of 2 mg/animal dramatically decreased tumor volume and suppressed local metastasis, which was more effective than cisplatin alone. Lupeol exerted a significant synergistic cytotoxic effect when combined with low-dose cisplatin without side effects. Our results suggest that lupeol may be an effective agent either alone or in combination for treatment of advanced tumors. [Cancer Res 2007;67(18):8800-9]

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Section: Introductionmentioning

confidence: 99%

Lupeol Suppresses Cisplatin-Induced Nuclear Factor-κB Activation in Head and Neck Squamous Cell Carcinoma and Inhibits Local Invasion and Nodal Metastasis in an Orthotopic Nude Mouse Model

Lee¹,

Poon²,

Wo³

et al. 2007

Cancer Research

114

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“…[24][25][26] In fact, inhibition of POLB expression has recently been used as a novel approach to increase sensitivity to cisplatinbased cancer therapy. 27 The 2 SNPs examined in the current study are both localized in the intron region (intron 10 and intron 2), and the functional significance of these SNPs has not been explored. It is tempting to speculate that the homozygous variants may confer a lower expression of POLB and thus an increased sensitivity to cytotoxic treatment and an improved survival.…”

Section: Discussionmentioning

confidence: 99%

Effects of base excision repair gene polymorphisms on pancreatic cancer survival

Li¹,

Jiao

et al. 2007

Intl Journal of Cancer

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To explore the association between single nucleotide polymorphisms of DNA repair genes and overall survival of patients with pancreatic cancer, we conducted a study in 378 cases of pancreatic adenocarcinoma who were treated at The University of Texas M. D. Anderson Cancer Center between February 1999 and October 2004 and were followed up to April 2006. Genotypes were determined using genomic DNA and the MassCode method. Overall survival was analyzed using the Kaplan-Meier plot, log-rank test and Cox regression. We observed a strong effect of the POLB A165G and T2133C genotypes on overall survival. The median survival time (MST) was 35.7 months for patients carrying at least 1 of the 2 homozygous variant POLB GG or CC genotypes, compared with 14.8 months for those carrying the AA/AG or TT/TC genotypes (p 5 0.02, log rank test). The homozygous variants of hOGG1 G2657A, APEX1 D148E and XRCC1 R194W polymorphisms all showed a weak but significant effect on overall survival as demonstrated by either log rank test or multivariate COX regression after adjusting for other potential confounders. In combined genotype analysis, a predominant effect of the POLB homozygous variants on survival was observed. When POLB was not included in the model, a slightly better survival was observed among those carrying none of the adverse genotypes than those carrying at least one of the adverse genotypes. These observations suggest that polymorphisms of base excision repair genes significantly affect the clinical outcome of patients with pancreatic cancer. These observations need to be confirmed in a larger study of homogenous patient population. ' 2007 Wiley-Liss, Inc.

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“…As mentioned above, Pol β is overexpressed in prostate, ovary, uterus and stomach cancers (38), whereas Polι is overexpressed in breast cancer (82) and Pol κ is overexpressed in lung cancer (83). Elevation in expression and activity of the error-prone polymerase, Pol β, accounts for the increase in cisplatin resistance and mutagenesis of many cancers (84). …”

Section: Dna Repair Genes and Cancer Initiationmentioning

confidence: 99%

DNA Damage Response Genes and the Development of Cancer Metastasis

Broustas¹,

Lieberman²

2014

Radiation Research

241

159

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DNA damage response genes play vital roles in the maintenance of a healthy genome. Defects in cell cycle checkpoint and DNA repair genes, especially mutation or aberrant downregulation, are associated with a wide spectrum of human disease, including a predisposition to the development of neurodegenerative conditions and cancer. On the other hand, upregulation of DNA damage response and repair genes can also cause cancer, as well as increase resistance of cancer cells to DNA damaging therapy. In recent years, it has become evident that many of the genes involved in DNA damage repair have additional roles in tumorigenesis, most prominently by acting as transcriptional (co-) factors. Although defects in these genes are causally connected to tumor initiation, their role in tumor progression is more controversial and it seems to depend on tumor type. In some tumors like melanoma, cell cycle checkpoint/DNA repair gene upregulation is associated with tumor metastasis, whereas in a number of other cancers the opposite has been observed. Several genes that participate in the DNA damage response, such as RAD9, PARP1, BRCA1, ATM and TP53 have been associated with metastasis by a number of in vitro biochemical and cellular assays, by examining human tumor specimens by immunohistochemistry or by DNA genomewide gene expression profiling. Many of these genes act as transcriptional effectors to regulate other genes implicated in the pathogenesis of cancer. Furthermore, they are aberrantly expressed in numerous human tumors and are causally related to tumorigenesis. However, whether the DNA damage repair function of these genes is required to promote metastasis or another activity is responsible (e.g., transcription control) has not been determined. Importantly, despite some compelling in vitro evidence, investigations are still needed to demonstrate the role of cell cycle checkpoint and DNA repair genes in regulating metastatic phenotypes in vivo.

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Modulation of Cellular Response to Cisplatin by a Novel Inhibitor of DNA Polymerase β

Cited by 51 publications

References 40 publications

Lupeol Suppresses Cisplatin-Induced Nuclear Factor-κB Activation in Head and Neck Squamous Cell Carcinoma and Inhibits Local Invasion and Nodal Metastasis in an Orthotopic Nude Mouse Model

Lupeol Suppresses Cisplatin-Induced Nuclear Factor-κB Activation in Head and Neck Squamous Cell Carcinoma and Inhibits Local Invasion and Nodal Metastasis in an Orthotopic Nude Mouse Model

Effects of base excision repair gene polymorphisms on pancreatic cancer survival

DNA Damage Response Genes and the Development of Cancer Metastasis

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