Contributory role of microRNAs in anti-cancer effects of small molecule inhibitor of telomerase (BIBR1532) on acute promyelocytic leukemia cell line

Telomerase-mediated immortalization and proliferation of tumor cells is a promising anti-cancer treatment strategy and development of potent telomerase inhibitors is believed to open new window of treatments in human malignancies. In the present study, we found that BIBR1532, a small molecule inhibi...

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Published in:European journal of pharmacology 2019-03, Vol.846, p.49-62
Main Authors: Pourbagheri-Sigaroodi, Atieh, Bashash, Davood, Safaroghli-Azar, Ava, Farshi-Paraasghari, Masoumeh, Momeny, Majid, Mansoor, Fahimeh Nemati, Ghaffari, Seyed H.
Format: Article
Language:English
Subjects:
BIBR1532
Leukemia
MicroRNA
NF-κB
Telomerase
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Summary:Telomerase-mediated immortalization and proliferation of tumor cells is a promising anti-cancer treatment strategy and development of potent telomerase inhibitors is believed to open new window of treatments in human malignancies. In the present study, we found that BIBR1532, a small molecule inhibitor of human telomerase, exerted cytotoxic effects on a panel of human cancer cells spanning from solid tumors to hematologic malignancies; however, as compared with solid tumors, leukemic cells were more sensitive to this inhibitor. This was independent of molecular status of p53 in the leukemic cells. The results of a miRNA PCR array revealed that BIBR1532-induced cytotoxic effects in NB4, the most sensitive cell line, was coupled with alteration in a substantial number of cancer-related miRNAs. Interestingly, most of these miRNAs were found to act as tumor suppressors with validated targets in cell cycle or nuclear factor (NF)-κB–mediated apoptosis. In accordance with a bioinformatics analysis, our experimental studies showed that BIBR1532-induced apoptosis is mediated, at least partly, by inhibition of NF-κB. Moreover, we found that the alteration in the expression of miRNAs was coupled with the alteration in the cell cycle progression. To sum up with, a straightforward interpretation of our results is that telomerase inhibition using BIBR1532 not only induced CDKN1A-mediated G1 arrest in NB4, but also resulted in a caspase-3-dependent apoptotic cell death mostly through suppression of NF-κB axis.
ISSN:0014-2999
1879-0712
DOI:10.1016/j.ejphar.2019.01.018