Inhibition of Telomerase Increases Resistance of Melanoma Cells to Temozolomide, but Not to Temozolomide Combined with Poly (ADP-Ribose) Polymerase Inhibitor

Tentori, Lucio; Portarena, Ilaria; Barbarino, Marcella; Balduzzi, Alessandra; Levati, Lauretta; Vergati, Matteo; Biroccio, Annamaria; Gold, Barry; Lombardi, Maria Luisa; Graziani, Grazia

doi:10.1124/mol.63.1.192

Cited by 36 publications

(17 citation statements)

References 38 publications

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“…Malignant glioma cells were sensitised to cisplatin by inhibition of telomerase (Kondo et al, 1998b). Furthermore, inhibition of telomerase resulted in increased sensitivity to cisplatin, but increased resistance to TMZ in melanoma cells (Tentori et al, 2003). Therefore, the relationship between levels of telomerase activity in tumour cells prior to anticancer therapies and their sensitivity to therapeutic agents may depend on the type of cell or treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, in the present study, TMZ-sensitive and -resistant malignant glioma cells express a similar high level of telomerase. As suggested by Tentori et al (2003), TMZ sensitivity seems to be dependent mainly on Aliquots of 1 mg protein extract were used for assay. The amplification products were applied to a 10% polyacrylamide gel and stained using SYBR Green.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of telomerase activity in malignant glioma cells correlates with their sensitivity to temozolomide

et al. 2003

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Temozolomide (TMZ, 3,-as-tetrazine-8-carboxamide) is a new alkylating agent with promising antitumour efficacy for malignant gliomas. The resistance of tumour cells to TMZ is primarily associated with levels of the alkylguanine alkyltransferase (AGT). O 6 -benzylguanine (O 6 -BG), an inhibitor for AGT, reduced resistance to TMZ. Recently, it has been demonstrated that chemosensitivity of tumour cells is related to a decline in telomerase activity. However, it is unknown if TMZ sensitivity of malignant glioma cells correlates with telomerase. In this study, using malignant glioma cells with low levels of AGT (U373-MG and U87-MG) and high levels of AGT (T98G), we investigated the association among AGT, telomerase, and TMZ sensitivity. U373-MG and U87-MG cells were sensitive to TMZ (IC 50 for a 2-day treatment ¼ 100 mM), while T98G cells were resistant to TMZ (IC 50 for a 2-day treatment 4500 mM). Treatment with TMZ (100 mM) suppressed telomerase activity in U373-MG and U87-MG cells in a time-dependent manner, but not in T98G cells. The downregulation of telomerase activity in U373-MG and U87-MG cells was due to inhibition of the human telomerase reverse-transcriptase (hTERT) gene expression at the transcriptional level. This inhibitory effect was induced by interfering with transcription factor Sp1 binding sites of the hTERT core promoter. Interestingly, O 6 -BG not only sensitised T98G cells to TMZ, but also suppressed telomerase activity. These findings suggest that response of malignant glioma cells to TMZ can be monitored by reduction in telomerase activity. Therefore, quantification of telomerase activity during or after treatment with TMZ may be a useful marker to detect treatment efficacy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of telomerase activity in malignant glioma cells correlates with their sensitivity to temozolomide

et al. 2003

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“…Recently, it has been demonstrated that inhibition of telomerase using the DN-hTERT construct not only limits the growth of tumor cells, but also sensitizes them to anti-neoplastic drugs (Misawa et al 2002, Tentori et al 2003. In this context, we recently used the DN-hTERT construct in order to demonstrate the involvement of telomerase in the chemosensitivity of melanoma cells.…”

Section: Dominant-negative Htertmentioning

confidence: 99%

Telomerase as a new target for the treatment of hormone-refractory prostate cancer

Biroccio¹,

Leonetti²

2004

Endocr Relat Cancer

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Prostate cancer is the leading cause of cancer-related deaths in men. Androgen ablation is the mainstay of treatment for advanced prostate cancer. This therapy is very effective in androgen-dependent cancer; however, these cancers eventually become androgen independent, rendering anti-androgen therapy ineffective. The exploration of novel modalities of treatment is therefore essential to improve the prognosis of this neoplasia.Telomeres are specialized heterochromatin structures that act as protective caps at the ends of chromosomes. Telomere maintenance in the majority of tumor cells is achieved by telomerase, a reverse transcriptase enzyme that catalyzes the synthesis of further telomeric DNA. Telomerase is detected in the majority of prostate cancers, but not in normal or benign prostatic hyperplasia tissue. Moreover, the human telomerase reverse transcriptase (hTERT) gene, the catalytic subunit of telomerase, is regulated by androgens as well as by different oncogenes including Her-2, Ras, c-Myc and Bcl-2, which seem to play an important role in prostate cancer progression. Thus, telomerase may represent a very good candidate for targeted therapy in prostate tumors. To inhibit telomere maintenance by telomerase, approaches that directly target either telomerase and telomeres or the telomerase regulatory mechanisms have been used. Moreover, strategies targeting telomerase-positive cells as a means to directly kill the tumor cells have been tested. This review summarizes the most promising results achieved by anti-telomerase strategy in different solid tumors. Most of the telomeraseassociated therapies described here have proved very promising for the treatment of prostate cancer. On the basis of the good results obtained and considering the multigenic defects of human tumors, including prostate cancer, the combination of anti-telomerase strategies with conventional drugs and/or molecules capable of interfering with oncogenic pathways could efficiently improve the response of this neoplasia.

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“…Here, addition of 3-aminobenzamide restored the cytotoxic effects of TZM. 25 In summary, the combined treatment of tumour cells in vitro and, more important, in vivo with chemotherapeutic compounds such as alkylating agents or topoisomerase-1 inhibitors and PARP inhibitors yielded beneficial effects such as increasing the number of DNA strand breaks, growth inhibition and cell killing and thus enhancement of the survival of tumour-bearing animals. But it also has to be noted that the components of any such combinatorial treatment have to be selected carefully to avoid deleterious effects.…”

Section: Cancer Therapymentioning

confidence: 99%

Poly(ADP‐ribosyl)ation inhibitors: Promising drug candidates for a wide variety of pathophysiologic conditions

Beneke

Diefenbach

Bürkle

2004

Intl Journal of Cancer

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Poly(ADP-ribose) polymerases are involved in many aspects of regulation of cellular functions. Using NAD ؉ as a substrate, they catalyse the covalent transfer of ADP-ribose units onto several acceptor proteins to form a branched ADP-ribose polymer. The best characterised and first discovered member of this multiprotein family is PARP-1. Its catalytic activity is markedly stimulated upon binding to DNA strand interruptions, and the resulting polymer is thought to function in chromatin relaxation as well as in signalling the presence of damage to DNA repair complexes and in regulating enzyme activities. Moderate activation of PARP-1 facilitates the efficient repair of DNA damage arising from monofunctional alkylating agents, reactive oxygen species or ionising radiation, but severe genotoxic stress leads to rapid energy consumption and subsequently to necrotic cell death. The latter aspect of PARP-1 activity has been implicated in the pathogenesis of various clinical conditions such as shock, ischaemia-reperfusion and diabetes. Inhibition of ADP-ribose polymer formation has been shown to be effective, on the one hand, in the treatment of cancer in combination with alkylating agents by suppressing DNA repair and thus driving tumour cells into apoptosis, and on the other hand it appears to be a promising drug target for the treatment of pathologic conditions involving oxidative stress. In view of the existence of several members of the PARP family in mammalian cells, one has to be aware of possible side effects but also of a wide spectrum of potential clinical applications, which calls for the development of more specific inhibitors. © 2004 Wiley-Liss, Inc. Key words: DNA damage; PARP; cancer chemotherapy; radiotherapy; ischaemia-reperfusion damage; diabetes; shock; Parkinson syndromePoly(ADP-ribosyl)ation is a posttranslational modification of proteins in eukaryotic cells performed by a family of NAD ϩ ADP-ribosyl transferases, the poly(ADP-ribose) polymerases (PARPs). NAD ϩ molecules as precursor are cleaved into nicotinamide and ADP-ribose moieties, and the latter are covalently attached to glutamic or aspartic acid residues of proteins, with PARP itself being the major acceptor. Poly(ADP-ribosyl)ation may alter the activity of acceptor protein, leading to inactivation due to the attachment of a highly complex, branched polymer carrying large numbers of negative charges (Fig. 1). The polymer is rapidly degraded by the enzyme poly(ADP-ribose) glycohydrolase (PARG), limiting the half-life of the polymer to approximately 1 min under conditions of DNA breakage. Poly(ADPribosyl)ation was originally discovered as an immediate response of cells to DNA strand-break-inducing agents, i.e., ionising radiation, alkylating agents and oxidants. Polymer formation in living cells after genotoxic stresses is mainly dependent on PARP-1 (encoded by the ADPRT gene), the first-discovered and best-investigated member of the PARP family. After binding of PARP-1 with its 2 zinc-fingers within the N-terminal DNA-binding domain to double...

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Inhibition of Telomerase Increases Resistance of Melanoma Cells to Temozolomide, but Not to Temozolomide Combined with Poly (ADP-Ribose) Polymerase Inhibitor

Cited by 36 publications

References 38 publications

Inhibition of telomerase activity in malignant glioma cells correlates with their sensitivity to temozolomide

Inhibition of telomerase activity in malignant glioma cells correlates with their sensitivity to temozolomide

Telomerase as a new target for the treatment of hormone-refractory prostate cancer

Poly(ADP‐ribosyl)ation inhibitors: Promising drug candidates for a wide variety of pathophysiologic conditions

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