Metallothionein expression in ovarian cancer in relation to histopathological parameters and molecular markers of prognosis

Hengstler, Jan G.; Pilch, Henryk; Schmidt, M; Dahlenburg, Heather; Sagemüller, J; Schiffer, Ilka B.; Oesch, Franz; Knapstein, P.; Kaina, Bernd; Berno, Tamara

doi:10.1002/1097-0215(20010320)95:2<121::aid-ijc1021>3.0.co;2-n

Cited by 59 publications

(64 citation statements)

References 28 publications

(29 reference statements)

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“…The tumor suppressor protein p53, often mutated in human tumors, regulates apoptosis and cell survival upon DNA damage (39)(40)(41)(42). Tumor cells with p53 mutations are often resistant to cytotoxic drugs, such as cisplatin (43)(44)(45). Given that PC-3 cells do not express tumor suppressor p53, our data indicate that the cytotoxic effects of PCNA-I1 were likely mediated by both p53-dependent and -independent pathways.…”

Section: Discussionmentioning

confidence: 83%

Antitumor Effects of a Novel Small Molecule Targeting PCNA Chromatin Association in Prostate Cancer

Dillehay

Dong

2014

Molecular Cancer Therapeutics

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Proliferating cell nuclear antigen (PCNA) plays an essential role in DNA replication and repair. Tumor cells express high levels of PCNA, identifying it as a potentially ideal target for cancer therapy. Previously, we identified nine compounds termed PCNA inhibitors (PCNA-Is) that bind directly to PCNA, stabilize PCNA trimer structure, reduce chromatin-associated PCNA, and selectively inhibit tumor cell growth. Of these compounds, PCNA-I1 is most potent. The purposes of this study were to further investigate the effects of targeting PCNA chromatin association on DNA damage and cytotoxicity and to evaluate the therapeutic potential of PCNA-I1 against tumors in mice. Given the important roles of tumor suppressor p53 in regulating sensitivity of tumor cells to chemotherapeutics, we performed studies in two human prostate cancer cell lines differing in p53 expression: LNCaP cells (wild-type p53) and PC-3 cells (p53-null). PCNA-I1 induced DNA damage and apoptosis in both LNCaP and PC-3 cells and enhanced DNA damage and apoptosis triggered by cisplatin. PCNA-I1 also induced autophagy in PC-3 cells. A short-term pretreatment with PCNA-I1 reduced colony formation by 50% in both cell lines. These data suggest that, unlike many other cytotoxic drugs, the effects of PCNA-I1 on tumor cells do not depend on expression of p53. Intravenous administrations of PCNA-I1 significantly retarded growth of LNCaP tumors of in nude mice without causing detectable effects on mouse body weight and hematology profiles. These data provide proof of concept that targeting PCNA chromatin association could be a novel and effective therapeutic approach for treatment of cancer. Mol Cancer Ther; 13(12); 2817-26. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 83%

Antitumor Effects of a Novel Small Molecule Targeting PCNA Chromatin Association in Prostate Cancer

Dillehay

Dong

2014

Molecular Cancer Therapeutics

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“…Metallothionein I encodes a metal-binding protein that functions in cell growth, repair and differentiation and has been implicated as a potential marker for tumor differentiation or cell proliferation. 28 Furthermore, metallothionein I also plays a protective role against DNA damage and apoptosis induced by oxidative or external stress and has been postulated to contribute to radiation resistance in tumor cells. 29 Other genes that were also differentially upregulated in HK1 cells include the MMP-10 gene, genes encoding MCP-3, CPR2, CDK inhibitor 2A and IGF binding protein 3 (BP-3) (Fig.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the H19 imprinting gene expression in human nasopharyngeal carcinoma by methylation

Tang

Goh

et al. 2003

Intl Journal of Cancer

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In East Asia and Singapore, the human nasopharyngeal carcinoma (NPC) presented clinically is mainly of the undifferentiated type. In contrast, the well-differentiated squamous NPC is more commonly detected in the West. To study the potential differences in carcinogenesis between undifferentiated and differentiated human NPC, we employed cDNA microarrays to isolate genes that might be specific for human undifferentiated NPC. One of the genes identified to be specifically upregulated in the undifferentiated human NPC cell line CNE-2 is the human imprinting gene H19. Interestingly, H19 is not expressed in the welldifferentiated human HK1 NPC cells. Northern blot and in situ hybridization analyses also confirmed that the H19 gene is strongly expressed in the undifferentiated CNE-2 human NPC cell line but not in the well-differentiated HK1 human NPC cell line. In situ hybridization and reverse transcriptasepolymerase chain reaction also demonstrated that H19 is specifically expressed in NPC biopsies and not in non-NPC human tissue biopsies. Furthermore, we demonstrated that deregulation of H19 gene expression in the well-differentiated human HK1 NPC cells could be induced by the hypomethylation of CpG sites of the H19 promoter region. Hypermethylation of gene promoter regions might therefore be an important epigenetic event that plays a role in the differentiation of human NPC cells and the transcriptional silencing of imprinted genes.

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“…This has been documented in vitro, by comparing the sensitivity to cisplatin of a wide panel of TP53-proficient and -deficient tumor cell lines (O'Connor et al, 1997;Branch et al, 2000), and also in vivo, in the clinical setting (Hengstler et al, 2001). Thus, ovarian cancer patients harboring wild-type TP53 reportedly have a higher probability to benefit from cisplatin-based chemotherapy than patients with TP53 mutations (Gadducci et al, 2002;Feldman et al, 2008).…”

Section: Mechanism Of Post-target Resistancementioning

confidence: 99%

Molecular mechanisms of cisplatin resistance

et al. 2011

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Platinum-based drugs, and in particular cis-diamminedichloroplatinum(II) (best known as cisplatin), are employed for the treatment of a wide array of solid malignancies, including testicular, ovarian, head and neck, colorectal, bladder and lung cancers. Cisplatin exerts anticancer effects via multiple mechanisms, yet its most prominent (and best understood) mode of action involves the generation of DNA lesions followed by the activation of the DNA damage response and the induction of mitochondrial apoptosis. Despite a consistent rate of initial responses, cisplatin treatment often results in the development of chemoresistance, leading to therapeutic failure. An intense research has been conducted during the past 30 years and several mechanisms that account for the cisplatin-resistant phenotype of tumor cells have been described. Here, we provide a systematic discussion of these mechanism by classifying them in alterations (1) that involve steps preceding the binding of cisplatin to DNA (pre-target resistance), (2) that directly relate to DNAcisplatin adducts (on-target resistance), (3) concerning the lethal signaling pathway(s) elicited by cisplatin-mediated DNA damage (post-target resistance) and (4) affecting molecular circuitries that do not present obvious links with cisplatin-elicited signals (off-target resistance). As in some clinical settings cisplatin constitutes the major therapeutic option, the development of chemosensitization strategies constitute a goal with important clinical implications.

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Metallothionein expression in ovarian cancer in relation to histopathological parameters and molecular markers of prognosis

Cited by 59 publications

References 28 publications

Antitumor Effects of a Novel Small Molecule Targeting PCNA Chromatin Association in Prostate Cancer

Antitumor Effects of a Novel Small Molecule Targeting PCNA Chromatin Association in Prostate Cancer

Regulation of the H19 imprinting gene expression in human nasopharyngeal carcinoma by methylation

Molecular mechanisms of cisplatin resistance

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