Raising the bar in anticancer therapy: recent advances in, and perspectives on, telomerase inhibitors

Saraswati, A Prasanth; Relitti, Nicola; Brindisi, Margherita; Gemma, Sandra; Zisterer, Daniela M.; Butini, Stefania; Campiani, Giuseppe

doi:10.1016/j.drudis.2019.05.015

Cited by 32 publications

(26 citation statements)

References 118 publications

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“…The main advantage of TERT is its high cancer-specific expression. Results from clinical trials have been encouraging, because of the safety and good tolerability of telomerase inhibitors ( 215 ). As a final point, it should be noted that using just one type immunotherapy may not suffice to eliminate cancer cells.…”

Section: Tert As a Potential Therapeutic Targetmentioning

confidence: 99%

TERT—Regulation and Roles in Cancer Formation

et al. 2020

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Telomerase reverse transcriptase (TERT) is a catalytic subunit of telomerase. Telomerase complex plays a key role in cancer formation by telomere dependent or independent mechanisms. Telomere maintenance mechanisms include complex TERT changes such as gene amplifications, TERT structural variants, TERT promoter germline and somatic mutations, TERT epigenetic changes, and alternative lengthening of telomere. All of them are cancer specific at tissue histotype and at single cell level. TERT expression is regulated in tumors via multiple genetic and epigenetic alterations which affect telomerase activity. Telomerase activity via TERT expression has an impact on telomere length and can be a useful marker in diagnosis and prognosis of various cancers and a new therapy approach. In this review we want to highlight the main roles of TERT in different mechanisms of cancer development and regulation.

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Section: Tert As a Potential Therapeutic Targetmentioning

confidence: 99%

TERT—Regulation and Roles in Cancer Formation

et al. 2020

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“…Due to this multilevel role in carcinogenesis, different strategies are under investigations for telomerase inhibition, such as gene silencing through siRNA or treatment with small molecules (10). BIBR1532 is a non-nucleosidic, non-peptidic inhibitor of telomerase that blocks enzymatic activity by binding to the active site of TERT (11).…”

Section: Introductionmentioning

confidence: 99%

“…BIBR1532 is a non-nucleosidic, non-peptidic inhibitor of telomerase that blocks enzymatic activity by binding to the active site of TERT (11). Treatment of many cancer cell types with this drug has been shown to efficiently repress TA, leading to growth arrest and cell death (10). Moreover, independently from its activity as functional telomerase inhibitor, BIBR1532 induces the down-regulation of TERT expression, which in turn further weakens TA and provides additional anti-cancer effects linked to impairment of its extra-telomeric functions (8,12).…”

Section: Introductionmentioning

confidence: 99%

The Small Molecule BIBR1532 Exerts Potential Anti-cancer Activities in Preclinical Models of Feline Oral Squamous Cell Carcinoma Through Inhibition of Telomerase Activity and Down-Regulation of TERT

et al. 2021

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Expression of telomerase reverse transcriptase (TERT) and telomerase activity (TA) is a main feature of cancer, contributing to cell immortalization by causing telomeres dysfunction. BIBR1532 is a potent telomerase inhibitor that showed potential anti-tumor activities in several types of cancer, by triggering replicative senescence and apoptosis. In a previous work, we detected, for the first time, TERT expression and TA in preclinical models of feline oral squamous cell carcinoma (FOSCC); therefore, we aimed at extending our investigation by testing the effects of treatment with BIBR1532, in order to explore the role of telomerase in this tumor and foreshadow the possibility of it being considered as a future therapeutic target. In the present study, treatment of FOSCC cell lines SCCF1, SCCF2, and SCCF3 with BIBR1532 resulted in successful inhibition of TA, with subsequent cell growth stoppage and decrease in cell viability. Molecular data showed that up-regulation of cell cycle inhibitor p21, unbalancing of Bax/Bcl-2 ratio, and down-regulation of survival gene Survivin were mostly involved in the observed cellular events. Moreover, BIBR1532 diminished the expression of TERT and its transcriptional activator cMyc, resulting in the down-regulation of epidermal growth factor receptor (EGFR), phospho-ERK/ERK ratio, and matrix metalloproteinases (MMPs)-1/-2 and−9, likely as a consequence of an impairment of TERT extra-telomeric functions. Taken together, our data suggest that BIBR1532 exerts multiple anti-cancer activities in FOSCC by inhibiting telomerase pathway and interfering with signaling routes involved in cell proliferation, cell survival, and invasion, paving the way for future translational studies aimed at evaluating its possible employment in the treatment of this severe tumor of cats.

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“…La structure G4 autorise en effet la conception de petites molécules les reconnaissant sélectivement, ce qui conduit à une inhibition indirecte de la télomérase. De très nombreux composés naturels ou synthétiques se sont révélés actifs par ce biais (pour revue [Saraswati 2019]); il faut cependant garder à l'esprit que le test TRAP (Telomerase repeat amplification protocol), communément utilisé pour mesurer l'activité télomérase, n'est pas adapté à l'évaluation de ces dérivés [De Cian 2007] : la télomestatine, dont la formule est présentée en Figure 1, peut inhiber la télomérase en stabilisant une configuration « bloquée » de son substrat, qui ne peut plus être allongée. Une telle inhibition est généralement mise en évidence par un test TRAP, et une IC 50 remarquable de 0,64 nM est alors déterminée.…”

Section: Stratégies Quadruplexunclassified