Contributory Role of Micrornas in Anti-Cancer Effects of Small Molecule Inhibitor of Telomerase (Bibr1532) on Acute Promyelocytic Leukemia Cell Line Publisher Pubmed



Pourbagherisigaroodi A² ; Bashash D¹ ; Safaroghliazar A³ ; Farshiparaasghari M³ ; Momeny M⁴ ; Mansoor FN² ; Ghaffari SH⁵
Source: European Journal of Pharmacology Published:2019

Abstract

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. © 2019 Elsevier B.V.