BIBR1532 Affects Endometrial Cell Proliferation, Migration, and Invasion in Endometriosis via Telomerase Inhibition and MAPK Signaling

Zhao, Xiaoling; Luo, Dan; Liu, Tingting; Kong, Weimin; Xie, Yunkai; Kong, Wei­min

doi:10.1159/000530460

Cited by 3 publications

(1 citation statement)

References 56 publications

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“…Notably, the immunoreactivity of proliferative markers, including telomerase, in baboon eutopic endometrial tissues was activated after the intrapelvic injection of menstrual endometrium and sustained for up to 15 months, indicating the development of a proliferative phenotype contributing to the establishment of endometriosis [ 55 ]. While telomerase inhibitors can effectively inhibit the growth, migration and invasion characteristics of ectopic lesions from endometriosis [ 56 ]. Therefore, we propose that both eutopic and ectopic endometrial tissues from patients with endometriosis exhibit proliferation beyond replicative senescence.…”

Section: Discussionmentioning

confidence: 99%

Causal association between telomere length and female reproductive endocrine diseases: a univariable and multivariable Mendelian randomization analysis

Yang,

Zhang,

Fan

2024

J Ovarian Res

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Background The relationship between leukocyte telomere length (LTL) and female reproductive endocrine diseases has gained significant attention and research interest in recent years. However, there is still limited understanding of the exact impacts of LTL on these diseases. Therefore, the primary objective of this study was to investigate the genetic causal association between LTL and female reproductive endocrine diseases by employing Mendelian randomization (MR) analysis. Methods Instruments for assessing genetic variation associated with exposure and outcome were derived from summary data of published genome-wide association studies (GWAS). Inverse-variance weighted (IVW) was utilized as the main analysis method to investigate the causal relationship between LTL and female reproductive endocrine diseases. The exposure data were obtained from the UK Biobanks GWAS dataset, comprising 472,174 participants of European ancestry. The outcome data were acquired from the FinnGen consortium, including abnormal uterine bleeding (menorrhagia and oligomenorrhea), endometriosis (ovarian endometrioma and adenomyosis), infertility, polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI) and premenstrual syndrome (PMS). Furthermore, to account for potential confounding factors such as smoking, alcohol consumption, insomnia, body mass index (BMI) and a history of pelvic inflammatory disease (PID), multivariable MR (MVMR) analysis was also conducted. Lastly, a series of pleiotropy tests and sensitivity analyses were performed to ensure the reliability and robustness of our findings. P < 0.0063 was considered to indicate statistically significant causality following Bonferroni correction. Results Our univariable MR analysis demonstrated that longer LTL was causally associated with an increased risk of menorrhagia (IVW: odds ratio [OR]: 1.1803; 95% confidence interval [CI]: 1.0880–1.2804; P = 0.0001) and ovarian endometrioma (IVW: OR: 1.2946; 95%CI: 1.0970–1.5278; P = 0.0022) at the Bonferroni significance level. However, no significant correlation was observed between LTL and oligomenorrhea (IVW: OR: 1.0124; 95%CI: 0.7350–1.3946; P = 0.9398), adenomyosis (IVW: OR: 1.1978; 95%CI: 0.9983–1.4372; P = 0.0522), infertility (IVW: OR: 1.0735; 95%CI: 0.9671–1.1915; P = 0.1828), PCOS (IVW: OR: 1.0633; 95%CI: 0.7919–1.4278; P = 0.6829), POI (IVW: OR: 0.8971; 95%CI: 0.5644–1.4257; P = 0.6459) or PMS (IVW: OR: 0.7749; 95%CI: 0.4137–1.4513; P = 0.4256). Reverse MR analysis indicated that female reproductive endocrine diseases have no causal effect on LTL. MVMR analysis suggested that the causal effect of LTL on menorrhagia and ovarian endometrioma remained significant after accounting for smoking, alcohol consumption, insomnia, BMI and a history of PID. Pleiotropic and sensitivity analyses also showed robustness of our results. Conclusion The results of our bidirectional two-sample MR analysis revealed that genetically predicted longer LTL significantly increased the risk of menorrhagia and ovarian endometrioma, which is consistent with the findings from MVMR studies. However, we did not notice any significant effects of LTL on oligomenorrhea, adenomyosis, infertility, PCOS, POI or PMS. Additionally, reproductive endocrine disorders were found to have no impact on LTL. To enhance our understanding of the effect and underlying mechanism of LTL on female reproductive endocrine diseases, further large-scale studies are warranted in the future.

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Section: Discussionmentioning

confidence: 99%

Causal association between telomere length and female reproductive endocrine diseases: a univariable and multivariable Mendelian randomization analysis

Yang,

Zhang,

Fan

2024

J Ovarian Res

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Dual-Targeted Microbubbles Promote Apoptosis of M1 Macrophages by Inhibiting Telomerase Activity for Atherosclerosis Therapy

Zeng,

Huang,

Huang

et al. 2024

Preprint

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It is known that M1 macrophages are the dominant phenotype in progressive atherosclerosis (AS). Studies have shown that telomerase in macrophages can be activated during the atherosclerosis formation, but how to regulate the telomerase activity of M1 macrophages is the focus of treatment of AS. Herein, we report a dual-targeted microbubbles delivery system encapsulating the telomerase inhibitor BIBR1532 (Ab-MMB1532), designed for precise targeted therapy of AS. The Ab-MMB1532exhibits excellent biocompatibility and remarkable targeting capability towards M1 macrophages with its targeting advantage notably accentuated under high shear forces. Furthermore, it significantly downregulates telomerase activity. Metabolomics analysis indicates that the decrease in telomerase activity upregulates the expression of aspartic acid, a key protein in the Caspase pathway of apotosis. In vivo, Ab-MMB1532efficiently targeted and accumulated within AS lesions, leading to significantly delay of the AS progression by inhibiting telomerase activity and promoting apoptosis of M1 macrophages after 4-week treatment. In summary, Ab-MMB1532provides a new approach for potentially safer and more effective treatment of AS in the future.

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BIBR1532 inhibits proliferation and metastasis of esophageal squamous cancer cells by inducing telomere dysregulation

Wang,

Li,

et al. 2025

World J Gastrointest Oncol

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BACKGROUND Esophageal squamous cell carcinoma (ESCC) is a malignant tumor with high morbidity and mortality, and easy to develop resistance to chemotherapeutic agents. Telomeres are DNA-protein complexes located at the termini of chromosomes in eukaryotic cells, which are unreplaceable in maintaining the stability and integrity of genome. Telomerase, an RNA-dependent DNA polymerase, play vital role in telomere length maintain, targeting telomerase is a promising therapeutic strategy for cancer. AIM To investigate the efficacy and underlying mechanisms of BIBR1532, a telomerase inhibitor, in ESCC. METHODS KYSE150 and KYSE410 cells were cultured and exposed to various concentrations of BIBR1532. Cell viability was assessed at 48 hours and 72 hours to determine the IC50 values. The effects of BIBR1532 on ESCC cell proliferation, migration, and cellular senescence were evaluated using the cell counting kit-8 assay, plate colony formation assay, scratch assay, transwell assay, and β-galactosidase staining, respectively. Western blotting was performed to detect the expression of proteins in BIBR1532-treated ESCC cells, such as human telomerase reverse transcriptase (hTERT), key molecules involved in DNA damage response (DDR) or cellular senescence, as well as telomere-binding proteins. Additionally, a tumor-bearing nude mouse model was established to evaluate the anti-cancer effect of BIBR1532 in vivo . RESULTS The IC50 values for KYSE150 and KYSE410 cells after 48 hours of BIBR1532 exposure were 48.53 μM and 39.59 μM, respectively. These values decreased to 37.22 μM and 22.71 μM, respectively, following a longer exposure of 72 hours. BIBR1532 exhibited dose-dependent effects on KYSE150 and KYSE410 cells, including decreased hTERT expression, inhibition of proliferation and metastasis, and induction of cellular senescence. Mechanistically, BIBR1532 upregulated the expression of the DDR protein, γ-H2AX, and activated the ataxia telangiectasia and Rad3-related protein (ATR)/ check point kinase 1 (CHK-1) and ataxia-telangiectasia mutated gene (ATM)/CHK2 pathways. BIBR1532 downregulated the expression of telomere-binding proteins, including telomeric-repeat binding factor 1 (TRF1), TRF2, protection of telomeres 1, and TIN2-interacting protein 1. In a nude mouse xenograft model, BIBR1532 significantly suppressed tumor growth, reduced hTERT expression, and increased γ-H2AX protein levels. Hematoxylin and eosin staining of various organs, including the heart, liver, spleen, lungs, and kidneys, revealed no apparent adverse effects. CONCLUSION BIBR1532 exerts anti-cancer effects on ESCC by inducing DDR through the ATR/CHK1 and ATM/CHK2 pathways and downregulating the expression of telomere-binding proteins.

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BIBR1532 Affects Endometrial Cell Proliferation, Migration, and Invasion in Endometriosis via Telomerase Inhibition and MAPK Signaling

Cited by 3 publications

References 56 publications

Causal association between telomere length and female reproductive endocrine diseases: a univariable and multivariable Mendelian randomization analysis

Causal association between telomere length and female reproductive endocrine diseases: a univariable and multivariable Mendelian randomization analysis

Dual-Targeted Microbubbles Promote Apoptosis of M1 Macrophages by Inhibiting Telomerase Activity for Atherosclerosis Therapy

BIBR1532 inhibits proliferation and metastasis of esophageal squamous cancer cells by inducing telomere dysregulation

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