Selective cytotoxicity and telomere damage in leukemia cells using the telomerase inhibitor BIBR1532

Eldaly, Hesham; Kull, Miriam; Zimmermann, Stefan; Pantić, Milena; Waller, Christiane; Martens, Uwe M.

doi:10.1182/blood-2003-12-4322

Cited by 126 publications

(76 citation statements)

References 40 publications

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“…In this study the IC 50 value for this direct effect was found to be in the range of 50-60 mM. 27,42 We found similar concentrations to be effective in T-PLL samples. In contrast, no significant effects were observed for normal unstimulated T cells.…”

Section: Discussionsupporting

confidence: 53%

Short telomeres and high telomerase activity in T-cell prolymphocytic leukemia

et al. 2007

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To test the role of telomere biology in T-cell prolymphocytic leukemia (T-PLL), a rare aggressive disease characterized by the expansion of a T-cell clone derived from immuno-competent post-thymic T-lymphocytes, we analyzed telomere length and telomerase activity in subsets of peripheral blood leukocytes from 11 newly diagnosed or relapsed patients with sporadic T-PLL. Telomere length values of the leukemic T cells (mean7s.d.: 1.5370.65 kb) were all below the 1st percentile of telomere length values observed in T cells from healthy agematched controls whereas telomere length of normal T-and B cells fell between the 1st and 99th percentile of the normal distribution. Leukemic T cells exhibited high levels of telomerase and were sensitive to the telomerase inhibitor BIBR1532 at doses that showed no effect on normal, unstimulated T cells. Targeting the short telomeres and telomerase activity in T-PLL seems an attractive strategy for the future treatment of this devastating disease.

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Section: Discussionsupporting

confidence: 53%

Short telomeres and high telomerase activity in T-cell prolymphocytic leukemia

et al. 2007

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“…Inhibition of enzymatic activity with small synthetic molecules allows the disruption of the replicative capacity of cancer cells; in this way, it is though that normal somatic cells will not be affected due to the absence of TERT activity. In vitro studies showed that BIBR1532, a noncompetitive inhibitor of both TERT and TERC [92], leads to cellular senescence reducing proliferation and telomere length [24] and is cytotoxic in high doses [28]. Additionally, a marked reduction of the tumorigenic potential of tumour cells treated with BIBR1532 was observed in a mouse xenograft model [24], with no adverse side effects and uncomplicated oral administration of the drug.…”

Section: Telomerase As a Therapeutic Targetmentioning

confidence: 99%

Telomerase promoter mutations in cancer: an emerging molecular biomarker?

et al. 2014

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Cell immortalization has been considered for a long time as a classic hallmark of cancer cells. Besides telomerase reactivation, such immortalization could be due to telomere maintenance through the "alternative mechanism of telomere lengthening" (ALT) but the mechanisms underlying both forms of reactivation remained elusive. Mutations in the coding region of telomerase gene are very rare in the cancer setting, despite being associated with some degenerative diseases. Recently, mutations in telomerase (TERT) gene promoter were found in sporadic and familial melanoma and subsequently in several cancer models, notably in gliomas, thyroid cancer and bladder cancer. The importance of these findings has been reinforced by the association of TERT mutations in some cancer types with tumour aggressiveness and patient survival. In the first part of this review, we summarize the data on the biology of telomeres and telomerase, available methodological approaches and nonneoplastic diseases associated with telomere dysfunction. In the second part, we review the information on telomerase expression and genetic alterations in the most relevant types of cancer (skin, thyroid, bladder and central nervous system) on record, and discuss the value of telomerase as a new biomarker with impact on the prognosis and survival of the patients and as a putative therapeutic target.

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“…In both cases, the toxic effect appears to derive more from damage of the structure of individual telomeres than from a direct effect at the level of telomerase although additional mechanisms cannot be excluded. 21,22 Our results demonstrate that (a) retinoids, including ATRA, a clinically approved drug, can target hTERT in cells from patients with myeloid leukemia for which retinoid maturation therapy has not been shown of high efficacy so far and (b) this targeting can result in telomere shortening and subsequent cell death. Although we are aware that our current results are based on a small number of patients, they clearly extend our previous studies reporting a targeting of telomerase expression by ATRA or a combination of RARa and RXR agonists in ATRAmaturation-resistant APL-derived NB4 cells.…”

Section: Retinoids Target Htert In Myeloid Leukemiasmentioning

confidence: 66%

Telomerase targeting by retinoids in cells from patients with myeloid leukemias of various subtypes, not only APL

et al. 2006

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Numerous strategies have been proposed to specifically inhibit telomerase (human telomerase reverse transcriptase (hTERT)) but to date only a few are clinically relevant in anticancer therapy. Recently, we have shown that long-term treatment with all-trans retinoic acid (ATRA), a compound clinically approved for differentiation therapy of acute promyelocytic leukemia (APL), represses hTERT in differentiation-resistant APL cell lines leading to telomere shortening and death. This signaling requires the co-activation of the retinoic acid receptor a (RARa) and the retinoic X receptor (RXR). In contrast to differentiationtherapy, which is only successful in this subtype of leukemia, the telomerase-targeted pathway could also be of use in non-APL. Here, we demonstrate that repression of hTERT occurs in fresh blasts cells from patients with myeloid leukemias of various subtypes exposed ex vivo to ATRA or synthetic retinoids. These results support the idea that, by hTERT targeting, retinoids can induce telomere shortening and cell death and their integration in therapy protocols for myeloid leukemias refractory to maturation should be considered. Leukemia (2006) IntroductionTelomerase is a ribonucleoprotein complex responsible for the maintenance of telomeres. Its activity is generally undetectable in normal somatic cells, while it is expressed in approximately 85% of the common cancers. Expression of the catalytic protein component of the telomerase complex, hTERT (human Telomerase Reverse Transcriptase) plays a fundamental role in cellular immortalization. Hematopoietic stem cells express telomerase, 1-3 but not at a sufficient level to fully maintain telomere length. It is acknowledged that a high level of telomerase activity is detected in acute myeloid leukemia (more than 10-fold compared to normal hematopoietic cells) and during progression of chronic myeloid leukemia (CML). [4][5][6][7][8] Telomere shortening has also been described associated with progression of myelodysplastic syndrome (MDS) to overt leukemia. 9,10 As most cancer cells are reliant on telomerase for their survival, it has become a promising target of anticancer therapy. Even though multiple strategies have been described to specifically inhibit telomerase in vitro, 11 most of them have not been tested yet in clinical trials or are not relevant because of their low efficacy and/or a high toxicity.Among myeloid leukemias, acute promyelocytic leukemia (APL) was found to be particularly sensitive to differentiation therapy using pharmacological doses of all-trans retinoic acid (ATRA), which induce remission of APL patients by stimulating differentiation of leukemic cells. [12][13][14] Recently, we identified a new maturation-independent pathway, by which ATRA exerts an antiproliferative activity through hTERT downregulation, leading to telomere shortening and cell death. [15][16][17] The significance and extension of this observation to malignancies resistant to retinoid-induced differentiation is currently unknown. Here, we questioned whether h...

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Selective cytotoxicity and telomere damage in leukemia cells using the telomerase inhibitor BIBR1532

Cited by 126 publications

References 40 publications

Short telomeres and high telomerase activity in T-cell prolymphocytic leukemia

Short telomeres and high telomerase activity in T-cell prolymphocytic leukemia

Telomerase promoter mutations in cancer: an emerging molecular biomarker?

Telomerase targeting by retinoids in cells from patients with myeloid leukemias of various subtypes, not only APL

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