BIBR 1532

BIBR 1532 is a novel, specific telomerase inhibitor with IC50 of 93 nM [1].

It has been reported that BIBR 1532 inhibited the reverse transcriptase of telomerase, hTERT, and shortened the length of the telomerase to suppress human cancer cell proliferation [1]. In pre-B acute lymphoblastic leukemia cells, BIBR1532 suppressed c-Myc and hTERT expression in a concentration-dependent manner to inhibit telomerase activity, and high doses of BIBR1532 could induce apoptosis by elevating p73, Bax/Bcl-2 and caspase-3 activation [2]. In NB4 leukemic cells, combined treatments with BIBR 1532 and arsenic trioxide suppressed cell proliferative capacity and inhibited telomerase activity probably via transcriptional suppression of c-Myc and hTERT. [4]

References:
[1]. Damm, K.; Hemmann, U.; Garin-Chesa, P.; Hauel, N.; Kauffman, I.; Priepke, H.; Niestroj, C.; Daiber, C.; Enenkel, B.; Guilliard, B.; Lauritsch, I.; Muller, E.; Pascolo, E.; Sauter, G.; Pantic, M.; Martens, U. M.; Wenz, C.; Linger, J.; Kraut, N.; Rettig, W. J.;Schnapp, A. A highly selective telomerase inhibitor limiting human cancer cell proliferation. EMBO J. 2001, 20, 6958−6968.
[2]. Bashash D1, Ghaffari SH, Mirzaee R, Alimoghaddam K, Ghavamzadeh A. Telomerase inhibition by non-nucleosidic compound BIBR1532 causes rapid cell death in pre-B acute lymphoblastic leukemia cells. Leuk Lymphoma. 2013 Mar;54[4]:561-8. doi: 10.3109/10428194.2012.704034. Epub 2012 Sep 28.
[3]. Bashash D1, Ghaffari SH, Zaker F, Kazerani M, Hezave K, Hassani S, Rostami M, Alimoghaddam K, Ghavamzadeh A. Anticancer Agents Med Chem. 2013 Sep;13(7):1115-25. BIBR 1532 increases arsenic trioxide-mediated apoptosis in acute promyelocytic leukemia cells: therapeutic potential for APL.

Glucose restriction decreases telomerase activity and enhances its inhibitor response on breast cancer cells: possible extra-telomerase role of BIBR 1532.[Pubmed:25089119]

Cancer Cell Int. 2014 Jul 4;14:60.

BACKGROUND: Considerable progress has been made to understand the association between lifestyle and diet in cancer initiation and promotion. Because excessive glucose consumption is a key metabolic hallmark of cancer cells, glucose restriction (GR) decreases the proliferation, and promotes the differentiation and transformation of cancer cells to quiescent cells. The immortality of cancerous cells is largely assured by telomerase, which is an interesting target for inhibition by BIBR 1532. In this study, we investigated the effect of GR on telomerase activity and on the efficacy of its inhibition by BIBR 1532. METHODS: Breast cancer MDA-MB 231 and MCF-7 cells were cultured in DMEM (Dulbecco's modified eagle's media) with 0, 1 or 4.5 g/l of glucose. The telomerase activity was measured via quantitative Real-Time PCR, and the two telomerase subunits were semi-quantified by RT-PCR. Proliferation test and mitochondrial metabolism were assessed via tetrazolium salt reduction and cell counts; apoptosis was assessed via caspase-3 quantification and flow cytometry. RESULTS: A decrease in the telomerase activity of more than 75% was associated with a significant reduction in the mRNA expression of its catalytic subunit hTERT (Reverse Transcriptase) and a decrease in the mitochondrial metabolism by more than 80% under restricted glucose conditions. In addition, GR increased the effect of BIBR 1532. Glucose deprivation induces apoptosis via BIBR 1532-mediated telomerase inhibition in triple negative breast cancer cells, as assessed by caspase-3 measurements and Annexin analysis. CONCLUSIONS: Taken together, our results suggest that the effect of BIBR 1532 is potentiated by GR to induce triple negative breast cancer cell death.

Direct short-term cytotoxic effects of BIBR 1532 on acute promyelocytic leukemia cells through induction of p21 coupled with downregulation of c-Myc and hTERT transcription.[Pubmed:22236190]

Cancer Invest. 2012 Jan;30(1):57-64.

Acute promyelocytic leukemia (APL) is characterized by specific t(15;17), distinct morphologic picture, and clinical coagulopathy that contribute to the morbidity and mortality of the disease. This study aims to investigate the effects of antitelomerase compound BIBR1532 on APL cells (NB4). BIBR 1532 exerts a direct short-term growth suppressive effect in a concentration-dependent manner probably through downregulation of c-Myc and hTERT expression. Our results also suggest that induction of p21 and subsequent disturbance of Bax/Bcl-2 balanced ratio as well as decreased telomerase activity may be rational mechanisms for the potent/direct short-term cytotoxicity of high doses of BIBR1532 against NB4 cells.

BIBR 1532 increases arsenic trioxide-mediated apoptosis in acute promyelocytic leukemia cells: therapeutic potential for APL.[Pubmed:23293885]

Anticancer Agents Med Chem. 2013 Sep;13(7):1115-25.

The current treatment of acute promyelocytic leukemia with arsenic trioxide (ATO) has increased long-lasting complete remissions; however, a proportion of patients continues to die eventually as a result of disease recurrence. In an effort to enhance the effectiveness of the APL treatment, we designed experiments to evaluate the effects of ATO in combination with the lead compound of non-nucleoside inhibitor of telomerase, BIBR 1532. After combined treatments with BIBR 1532 and ATO, decreased cell viability index with a concomitant increase in apoptotic cell death was observed in NB4 leukemic cells. Apoptosis induced by the combined treatments was accompanied by elevated Bax/Bcl-2 molecular ratio and enhanced caspase 3 activation. Our study has also demonstrated that the combined treatment suppressed NB4 cell proliferative capacity and inhibited telomerase activity probably via transcriptional suppression of c-Myc and hTERT. In conclusion, this study may supply insight into the application of this new combination therapy to APL cells intrinsically less sensitive to routine therapies and suggested a novel combination therapy for patients with more aggressive disease; those who may not respond favorably to the arsenic mono-therapy.

Inhibition of telomerase by BIBR 1532 and related analogues.[Pubmed:12657276]

Bioorg Med Chem Lett. 2003 Apr 7;13(7):1333-6.

BIBR 1532 has been reported to be a potent, small molecule inhibitor of human telomerase, suggesting it as a lead for the development of anti-telomerase therapy. We confirm the ability of BIBR 1532 to inhibit telomerase and report the discovery of an equally potent analogue. Importantly, IC(50) values in cell extract are considerably higher than those previously reported using assays for purified enzyme, indicating that substantial improvement may be necessary.

Telomerase inhibitors and 'T-oligo' as cancer therapeutics: contrasting molecular mechanisms of cytotoxicity.[Pubmed:18454043]

Anticancer Drugs. 2008 Apr;19(4):329-38.

Telomeres, the specialized structures that comprise the ends of chromosomes, form a closed structure, or t-loop, that is important in preventing genomic instability. Forced modulation of this structure, via overexpression of a dominant-negative form of telomere repeat binding factor 2, a protein critical for maintaining t-loop structure, for example, can result in the activation of DNA-damage responses, and ultimately cellular senescence or apoptosis. This response is also seen in normal somatic cells, where telomeres steadily decrease in length as cellular proliferation occurs owing to inefficient replication of terminal telomeric DNA. When telomere length becomes critically short, t-loop structure is compromised, and the cell undergoes senescence. Telomerase, the enzyme responsible for telomere length maintenance, is overexpressed in a majority of cancers. Its lack of expression in most normal somatic cells makes it an attractive target in designing cancer therapeutics. Compounds currently under development that seek to inhibit hTERT, the reverse transcriptase component of telomerase, include nucleoside analogs and the small molecule BIBR1532. Compounds inhibiting the RNA component of telomerase, hTERC, include peptide nucleic acids, 2-5A antisense oligonucleotides, and N3'-P5' thio-phosphoramidates. Recently, an oligonucleotide sharing sequence homology with terminal telomeric DNA, termed 'T-oligo', has shown cytotoxic effects in multiple cancers in culture and animal models. Independent of telomerase function, T-oligo is thought to mimic the DNA-damage response a cell normally experiences when the telomere t-loop structure becomes dysfunctional. In this review, the molecular mechanisms attributed to telomerase inhibitors and T-oligo, as well as their potential as cancer therapeutics, are discussed.

Telomerase and its potential for therapeutic intervention.[Pubmed:17603541]

Br J Pharmacol. 2007 Dec;152(7):1003-11.

Telomerase and telomeres are attractive targets for anticancer therapy. This is supported by the fact that the majority of human cancers express the enzyme telomerase which is essential to maintain their telomere length and thus, to ensure indefinite cell proliferation--a hallmark of cancer. Tumours have relatively shorter telomeres compared to normal cell types, opening the possibility that human cancers may be considerably more susceptible to killing by agents that inhibit telomere replication than normal cells. Advances in the understanding of the regulation of telomerase activity and the telomere structure, as well as the identification of telomerase and telomere associated binding proteins have opened new avenues for therapeutic intervention. Here, we review telomere and telomerase biology and the various approaches which have been developed to inhibit the telomere/telomerase complex over the past decade. They include inhibitors of the enzyme catalytic subunit and RNA component, agents that target telomeres, telomerase vaccines and drugs targeting binding proteins. The emerging role of telomerase in cancer stem cells and the implications for cancer therapy are also discussed.

A highly selective telomerase inhibitor limiting human cancer cell proliferation.[Pubmed:11742973]

EMBO J. 2001 Dec 17;20(24):6958-68.

Telomerase, the ribonucleoprotein enzyme maintaining the telomeres of eukaryotic chromosomes, is active in most human cancers and in germline cells but, with few exceptions, not in normal human somatic tissues. Telomere maintenance is essential to the replicative potential of malignant cells and the inhibition of telomerase can lead to telomere shortening and cessation of unrestrained proliferation. We describe novel chemical compounds which selectively inhibit telomerase in vitro and in vivo. Treatment of cancer cells with these inhibitors leads to progressive telomere shortening, with no acute cytotoxicity, but a proliferation arrest after a characteristic lag period with hallmarks of senescence, including morphological, mitotic and chromosomal aberrations and altered patterns of gene expression. Telomerase inhibition and telomere shortening also result in a marked reduction of the tumorigenic potential of drug-treated tumour cells in a mouse xenograft model. This model was also used to demonstrate in vivo efficacy with no adverse side effects and uncomplicated oral administration of the inhibitor. These findings indicate that potent and selective, non-nucleosidic telomerase inhibitors can be designed as novel cancer treatment modalities.