This letter addresses challenges in the clinical translation of BIBR1532,a promising telomerase inhibitor,for the treatment of esophageal squamous cell carcinoma(ESCC).BIBR1532 exerts its anti-cancer effect by activat...This letter addresses challenges in the clinical translation of BIBR1532,a promising telomerase inhibitor,for the treatment of esophageal squamous cell carcinoma(ESCC).BIBR1532 exerts its anti-cancer effect by activating DNA damage response(ATR/CHK1 and ATM/CHK2)pathways and downregulating telomere-binding proteins.Although its therapeutic potential is limited by poor aqueous solubility,solid dispersion(SD)technology may overcome this obstacle.Systematic analysis using PubChem-derived simplified molecular input line entry system identifiers and artificial intelligence-driven FormulationDT platform evaluation(oral formulation feasibility index:0.38)revealed that the SD technology,with superior scalability(32 approved products by 2021)and lower production risks,outperforms lipid-based formulations as an optimal dissolution strategy.Material analysis revealed hydroxypropyl methylcellulose(HPMC)as the optimal carrier with lower hygroscopicity,higher temperature and no intestinal targeting,thus enabling ESCC therapy.HPMC-based SD enhances BIBR1532 solubility and bioavailability for effective ESCC treatment.Future studies should focus on pilot tests for SD fabrication.展开更多
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 te...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 chro-mosomes 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.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,andβ-galactosidase staining,respectively.Western blotting was performed to detect the expression of RESULTS The IC50 values for KYSE150 and KYSE410 cells after 48 hours of BIBR1532 exposure were 48.53μM and 39.59μM,respectively.These values decreased to 37.22μM and 22.71μM,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 increasedγ-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.展开更多
Organic-inorganic hybrids have shown great potential for assembling dielectric phase transition materials,due to their unique characteristics and structural diversities.Here,we construct a new organic-organic hybrid,(...Organic-inorganic hybrids have shown great potential for assembling dielectric phase transition materials,due to their unique characteristics and structural diversities.Here,we construct a new organic-organic hybrid,(cyclopropylaminium)_(3)BiBr_(6)(1),which consists of a zero-dimensional inorganic framework of BiBr_(6)octahedra and ternary cyclic organic cations.展开更多
基金Supported by“Continuation”Project of Excellent Doctors,Guangdong Basic and Applied Basic Research Foundation,No.2025A04J5082Guangdong Basic and Applied Basic Research Foundation,No.2024A1515011236.
文摘This letter addresses challenges in the clinical translation of BIBR1532,a promising telomerase inhibitor,for the treatment of esophageal squamous cell carcinoma(ESCC).BIBR1532 exerts its anti-cancer effect by activating DNA damage response(ATR/CHK1 and ATM/CHK2)pathways and downregulating telomere-binding proteins.Although its therapeutic potential is limited by poor aqueous solubility,solid dispersion(SD)technology may overcome this obstacle.Systematic analysis using PubChem-derived simplified molecular input line entry system identifiers and artificial intelligence-driven FormulationDT platform evaluation(oral formulation feasibility index:0.38)revealed that the SD technology,with superior scalability(32 approved products by 2021)and lower production risks,outperforms lipid-based formulations as an optimal dissolution strategy.Material analysis revealed hydroxypropyl methylcellulose(HPMC)as the optimal carrier with lower hygroscopicity,higher temperature and no intestinal targeting,thus enabling ESCC therapy.HPMC-based SD enhances BIBR1532 solubility and bioavailability for effective ESCC treatment.Future studies should focus on pilot tests for SD fabrication.
基金Supported by the Scientific Research Development Plan Project or the Scientific Research Foundation for Advanced Talents,Affiliated Hospital of North Sichuan Medical College,No.2023MPZK017,No.2023ZD001,No.2023-2ZD002,and No.2023GC009Science and Technology Support Program of Nanchong,No.22SXQT0001+1 种基金Youth Medical Innovation Research Project,or Medical Research Project of Sichuan Province,No.Q23047 and No.S23020Development of a Scientific Research Plan for the Doctoral Scientific Research Foundation of the North Sichuan Medical College,No.CBY22-ZDA03.
文摘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 chro-mosomes 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.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,andβ-galactosidase staining,respectively.Western blotting was performed to detect the expression of RESULTS The IC50 values for KYSE150 and KYSE410 cells after 48 hours of BIBR1532 exposure were 48.53μM and 39.59μM,respectively.These values decreased to 37.22μM and 22.71μM,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 increasedγ-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.
基金supported by the National Natural Science Foundation of China(21875251,21622108,21833010,21525104)the NSF of Fujian Province(2018H0047)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB20010200).
文摘Organic-inorganic hybrids have shown great potential for assembling dielectric phase transition materials,due to their unique characteristics and structural diversities.Here,we construct a new organic-organic hybrid,(cyclopropylaminium)_(3)BiBr_(6)(1),which consists of a zero-dimensional inorganic framework of BiBr_(6)octahedra and ternary cyclic organic cations.
