Telomerase inhibition on acute myeloid leukemia stem cell induced apoptosis with both intrinsic and extrinsic pathways

Rafat, Ali; Asl, Khadijeh Dizaji; Mazloumi, Zeinab; Movassaghpour, Ali Akbar; Talebi, Mehdi; Shanehbandi, Dariush; Farahzadi, Raheleh; Nejati, Babak; Charoudeh, Hojjatollah Nozad

doi:10.1016/j.lfs.2022.120402

Cited by 19 publications

(8 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Treatment with TXT2 and TXT4 led to the activation of both Bid and Bax, which indicates the activation of extrinsic apoptosis involving transmembrane receptor-mediated interactions. Our observations are supported by an earlier study showing that inhibition of telomerase induced both intrinsic and extrinsic apoptosis in acute myeloid leukemia stem cells [ 43 ]. Shammas and co-workers reported that siRNA-mediated inhibition of telomerase activated both mitochondrial- and death-receptor-mediated pathways in Barrett’s adenocarcinoma SEG-1 cells [ 44 ].…”

Section: Discussionsupporting

confidence: 91%

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

et al. 2022

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 91%

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

et al. 2022

View full text Add to dashboard Cite

show abstract

“…BIBR1532 has been used in several studies as a specific and powerful telomerase inhibitor [ 48 , 73 , 74 , 75 ]. It demonstrates anti-migration and anti-proliferation properties in addition to its cytotoxic effect on cancer cells [ 76 , 77 ]. Recent clinical trials using a different telomerase inhibitor (Imetelstat) showed promising results against multiple myeloma, myelodysplasia, acute myeloid leukemia, and myelofibrosis, even in patients presenting resistance to first-line treatment options [ 78 , 79 , 80 , 81 , 82 , 83 ].…”

Section: Discussionmentioning

confidence: 99%

Consecutive Inhibition of Telomerase and Alternative Lengthening Pathway Promotes Hodgkin’s Lymphoma Cell Death

et al. 2022

View full text Add to dashboard Cite

Telomere maintenance is key during cancer development. Malignant cells can either use telomerase or an alternative lengthening of telomere (ALT) pathway to maintain their telomere length. In Hodgkin’s Lymphoma (HL), the presence of telomerase activation is established. The activation of ALT has been reported recently. Our data confirm this notion describing co-localization of the phosphorylated form of telomeric repeat-binding factor 1 (pT371-TRF1) with ALT-associated promyelocytic leukemia bodies. Surprisingly, to our knowledge, there are no published studies targeting both telomere maintenance pathways in HL. Consequently, we investigated, for the first time, the effects of both telomerase and ALT inhibition on HL cell viability: We inhibited telomerase and/or ALT, given either individually, simultaneously, or consecutively. We report that the inhibition of telomerase using BIBR1532 followed by ALT inhibition, using trabectedin, caused a decrease of greater than 90% in cell viability in three patient-derived HL cell lines. Our results suggest that HL cells are most vulnerable to the consecutive inhibition of telomerase followed by ALT inhibition.

show abstract

“…General apoptosis signaling (caspases 1 and 3–9) was determined by the peptide‐based pancaspase method. In brief, the cells were incubated with an annexin V/7AAD reagent 29,30 (Strong Biotech; Taipei, Taiwan) or a pancaspase kit (Abcam, Cambridge, UK), 31 according to the manufacturer's instructions. Finally, the fluorescent intensity was detected by a flow cytometer.…”

Section: Methodsmentioning

confidence: 99%

The neddylation inhibitor MLN4924 inhibits proliferation and triggers apoptosis of oral cancer cells but not for normal cells

Chen,

Chan,

Shiau

et al. 2023

Environmental Toxicology

View full text Add to dashboard Cite

Increased neddylation benefits the survival of several types of cancer cells. The inhibition of neddylation has the potential to exert anticancer effects but is rarely assessed in oral cancer cells. This study aimed to investigate the antiproliferation potential of a neddylation inhibitor MLN4924 (pevonedistat) for oral cancer cells. MLN4924 inhibited the cell viability of oral cancer cells more than that of normal oral cells (HGF‐1) with 100% viability, that is, IC50 values of oral cancer cells (CAL 27, OC‐2, and Ca9‐22) are 1.8, 1.4, and 1.9 μM. MLN4924 caused apoptotic changes such as the subG1 accumulation, activation of annexin V, pancaspase, and caspases 3/8/9 of oral cancer cells at a greater rate than in normal oral cells. MLN4924 induced greater oxidative stress in oral cancer cells compared to normal cells by upregulating reactive oxygen species and mitochondrial superoxide and depleting the mitochondrial membrane potential and glutathione. In oral cancer cells, preferential inductions also occurred for DNA damage (γH2AX and 8‐oxo‐2′‐deoxyguanosine). Therefore, this investigation demonstrates that MLN4924 is a potential anti‐oral‐cancer agent showing preferential inhibition of apoptosis and promotion of DNA damage with fewer cytotoxic effects on normal cells.

show abstract

Telomerase inhibition on acute myeloid leukemia stem cell induced apoptosis with both intrinsic and extrinsic pathways

Cited by 19 publications

References 41 publications

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

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

Consecutive Inhibition of Telomerase and Alternative Lengthening Pathway Promotes Hodgkin’s Lymphoma Cell Death

The neddylation inhibitor MLN4924 inhibits proliferation and triggers apoptosis of oral cancer cells but not for normal cells

Contact Info

Product

Resources

About