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- Title
Combinatorial targeting of telomerase and DNA-PK induces synergistic apoptotic effects against Pre-B acute lymphoblastic leukemia cells.
- Authors
Katoueezadeh, Maryam; Maleki, Parisa; Torabizadeh, Seyedeh Atekeh; Farsinejad, Alireza; Khalilabadi, Roohollah Mirzaee; Valandani, Hajar Mardani; Nurain, Ismaila Olanrewaju; Ashoub, Muhammad Hossein; Fatemi, Ahmad
- Abstract
Background: Due to the high demand for novel approaches for leukemia-targeted therapy, this study investigates the impact of DNA-PK inhibitor NU7441 on the sensitivity of pre-B ALL cells to the telomerase inhibitor MST-312. Methods: The study involved NALM-6 cells treated with MST-312 and NU7441, assessing their viability and metabolic activity using trypan blue and MTT assays. The study also evaluated apoptosis, gene expression changes, and DNA damage using flow cytometry, qRT-PCR, and micronucleus assays. The binding energy of MST-312 in the active site of telomerase was calculated using molecular docking. Results: The study’s findings revealed a synergistic decline in both cell viability and metabolic activity in NALM-6 cells when exposed to the combined treatment of MST-312 and NU7441, and this decrease occurred without any adverse effects on healthy PBMC cells. Furthermore, the combination treatment exhibited a significantly higher induction of apoptosis than treatment with MST-312 alone, as observed through flow cytometry assay. qRT-PCR analysis revealed that this enhanced apoptosis was associated with a notable downregulation of Bcl-2 expression and an upregulation of Bax gene expression. Moreover, the combination therapy decreased expression levels of hTERT and c-Myc genes. The micronucleus assay indicated that the combination treatment increased DNA damage in NALM-6 cells. Also, a good conformation between MST-312 and the active site of telomerase was revealed by docking data. Conclusions: The study suggests that simultaneous inhibition of telomerase and DNA-PK in pre-B ALL presents a novel targeted therapy approach.Highlights: MST-312/NU7441 exerts a synergistic cytotoxic effect against NALM-6 cells. NU7441 accentuates MST-312-induced apoptosis of NALM-6 cells. MST-312/NU7441-induced apoptosis progresses through upregulation of the Bax/Bcl-2 ratio. A combination of MST-312/NU7441 downregulates c-Myc and hTERT gene expression. NU7441 increases MST-312-induced DNA damage in NALM-6 cells.
- Publication
Molecular Biology Reports, 2024, Vol 51, Issue 1, p1
- ISSN
0301-4851
- Publication type
Article
- DOI
10.1007/s11033-023-09087-9