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Anti-Proliferative and Pro-Apoptotic Effects of Short-Term Inhibition of Telomerase In Vivo and in Human Malignant B Cells Xenografted in Zebrafish.

ABSTRACT: Besides its canonical role in stabilizing telomeres, telomerase reverse transcriptase (TERT) may promote tumor growth/progression through extra-telomeric functions. Our previous in vitro studies demonstrated that short-term TERT inhibition by BIBR1532 (BIBR), an inhibitor of TERT catalytic activity, negatively impacts cell proliferation and viability via telomeres' length-independent mechanism. Here we evaluate the anti-proliferative and pro-apoptotic effects of short-term telomerase inhibition in vivo in wild-type (wt) and tert mutant (terthu3430/hu3430; tert-/-) zebrafish embryos, and in malignant human B cells xenografted in casper zebrafish embryos. Short-term Tert inhibition by BIBR in wt embryos reduced cell proliferation, induced an accumulation of cells in S-phase and ultimately led to apoptosis associated with the activation of DNA damage response; all these effects were unrelated to telomere shortening/dysfunction. BIBR treatment showed no effects in tert-/- embryos. Xenografted untreated malignant B cells proliferated in zebrafish embryos, while BIBR pretreated cells constantly decreased and were significantly less than those in the controls from 24 to up to 72 h after xenotransplantation. Additionally, xenografted tumor cells, treated with BIBR prior- or post-transplantation, displayed a significant higher apoptotic rate compared to untreated control cells. In conclusion, our data demonstrate that short-term telomerase inhibition impairs proliferation and viability in vivo and in human malignant B cells xenografted in zebrafish, thus supporting therapeutic applications of TERT inhibitors in human malignancies.

SUBMITTER: Giunco S

PROVIDER: S-EPMC7463531 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Anti-Proliferative and Pro-Apoptotic Effects of Short-Term Inhibition of Telomerase In Vivo and in Human Malignant B Cells Xenografted in Zebrafish.

Giunco Silvia S Zangrossi Manuela M Dal Pozzolo Francesca F Celeghin Andrea A Ballin Giovanni G Petrara Maria Raffaella MR Amin Aamir A Argenton Francesco F Godinho Ferreira Miguel M De Rossi Anita A

Cancers 20200725 8

Besides its canonical role in stabilizing telomeres, telomerase reverse transcriptase (TERT) may promote tumor growth/progression through extra-telomeric functions. Our previous in vitro studies demonstrated that short-term TERT inhibition by BIBR1532 (BIBR), an inhibitor of TERT catalytic activity, negatively impacts cell proliferation and viability via telomeres' length-independent mechanism. Here we evaluate the anti-proliferative and pro-apoptotic effects of short-term telomerase inhibition ...[more]

PMID: 32722398

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Project description:Prostate cancer is a leading of cause of cancer related death in men. Despite intensive investment in improving early diagnosis, it often escapes timely detection. Mortality remains high in advanced stage prostate cancer where palliative care remains the only option. Effective strategies are therefore needed to prevent the occurrence and progression of the disease. Plant-derived compounds have been an important source of several clinically useful anti-cancer agents and offer an attractive approach against prostate cancer. We previously showed that the methanol extract of Maytenus royleanus (MEM) leaves and its fractions possess significant antioxidant activity with therapeutic potential against free-radical associated damages. The present study evaluated the anti-proliferative activity of MEM in the prostate cancer model system. Analysis of MEM and its various fractions revealed the presence of triterpenoids, flavonoids and tannins, conjugated to one or more polar groups and carbohydrate moieties. Further studies against known standards established the existence of caffeic acid and quercetin 3-rhamnoside in varying concentration in different MEM fractions. Time course analysis of MEM treated prostate cancer cells indicated significant decrease in cell viability, assessed by MTT and clonogenic survival assays. This was accompanied by G2 phase arrest of cell cycle, downregulation of cyclin/cdk network and increase in cdk inhibitors. MEM treated cells exhibited cleavage of Caspase-3 and PARP, and modulation of apoptotic proteins, establishing apoptosis as the primary mechanism of cell death. Notably MEM suppressed AR/PSA signaling both in prostate cancer cell cultures and in the in vivo model. Intraperitoneal injection of MEM (1.25 and 2.5 mg/ animal) to athymic nude mice implanted with androgen sensitive CWR22R?1 cells showed significant inhibition in tumor growth and decreased serum PSA levels reciprocating in vitro findings. Taken together, our data suggest that MEM may be explored further for its potential therapeutic effects against prostate cancer progression in humans.

Dataset Information

Anti-Proliferative and Pro-Apoptotic Effects of Short-Term Inhibition of Telomerase In Vivo and in Human Malignant B Cells Xenografted in Zebrafish.

Publications

Anti-Proliferative and Pro-Apoptotic Effects of Short-Term Inhibition of Telomerase In Vivo and in Human Malignant B Cells Xenografted in Zebrafish.

Similar Datasets

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