Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres - Publication - Bridge of Knowledge

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Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres

Abstract

Telomerase reactivation is one of the hallmarks of cancer, which plays an important role in cellular immortalization and the development and progression of the tumor. Chemical telomerase inhibitors have been shown to trigger replicative senescence and apoptotic cell death both in vitro and in vivo. Due to its upregulation in various cancers, telomerase is considered a potential target in cancer therapy. In this study, we identified potent, small-molecule telomerase inhibitors using a telomerase repeat amplification protocol assay. The results of the assay are the first evidence of telomerase inhibition by anthraquinone derivatives that do not exhibit G-quadruplex-stabilizing properties. The stability of telomerase in the presence of its inhibitor was evaluated under nearly physiological conditions using a cellular thermal shift assay. Our data showed that the compound induced aggregation of the catalytic subunit (hTERT) of human telomerase, and molecular studies confirmed the binding of the hit compound with the active site of the enzyme. The ability of new derivatives to activate DNA double-strand breaks (DSBs) was determined by high-resolution microscopy and flow cytometry in tumor cell lines differing in telomere elongation mechanism. The compounds triggered DSBs in TERT-positive A549 and H460 lung cancer cell lines, but not in TERT-negative NHBE normal human bronchial epithelial and ALT-positive U2OS osteosarcoma cell lines, which indicates that the induction of DSBs was dependent on telomerase inhibition. The observed DNA damage activated DNA damage response pathways involving ATM/Chk2 and ATR/Chk1 cascades. Additionally, the compounds induced apoptotic cell death through extrinsic and intrinsic pathways in lung cancer cells. Taken together, our study demonstrated that anthraquinone derivatives can be further developed into novel telomerase-related anticancer agents.

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DOI:
Digital Object Identifier (open in new tab) 10.1038/s41419-022-05443-y
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Details

Category:
Articles
Type:
artykuły w czasopismach
Published in:
Cell Death and Disease no. 13,
ISSN: 2041-4889
Language:
English
Publication year:
2022
Bibliographic description:
Maciejewska N., Olszewski M., Jurasz J., Bagiński M., Maryna S., Viktor Z., Folini M., Zaffaroni N.: Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres// Cell Death and Disease -Vol. 13,iss. 11 (2022), s.1005-
DOI:
Digital Object Identifier (open in new tab) 10.1038/s41419-022-05443-y
Sources of funding:
  • COST_FREE
Verified by:
Gdańsk University of Technology

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