Objective:To evaluate the efficacy of ponatinib plus gossypol against colorectal cancer HCT-116 and Caco-2 cells.Methods:Cells were treated with ponatinib and/or gossypol at increasing concentrations to evaluate syner...Objective:To evaluate the efficacy of ponatinib plus gossypol against colorectal cancer HCT-116 and Caco-2 cells.Methods:Cells were treated with ponatinib and/or gossypol at increasing concentrations to evaluate synergistic drug interactions by combination index.Cell viability,FGF19/FGFR4,and apoptotic and autophagic cell death were studied.Results:Ponatinib(1.25-40μM)and gossypol(2.5-80μM)monotherapy inhibited HCT-116 and Caco-2 cell viability in a doseand time-dependent manner.The combination of ponatinib and gossypol at a ratio of 1 to 2 significantly decreased cell viability(P<0.05),with a>2-and>4-fold reduction in IC50,respectively,after 24 h and 48 h,as compared to the IC50 of ponatinib.Lower combined concentrations showed greater synergism(combination index<1)with a higher ponatinib dose reduction index.Moreover,ponatinib plus gossypol induced morphological changes in HCT-116and Caco-2 cells,increased beclin-1 and caspase-3,and decreased FGF19,FGFR4,Bcl-2 and p-Akt as compared to treatment with drugs alone.Conclusions:Gossypol enhances ponatinib's anticancer effects against colorectal cancer cells through antiproliferative,apoptotic,and autophagic mechanisms.This may open the way for the future use of ponatinib at lower doses with gossypol as a potentially safer targeted strategy for colorectal cancer treatment.展开更多
Metastasis is the leading cause of human cancer deaths.Unfortunately,no approved drugs are available for antimetastatic treatment.In our study,high-throughput sequencing-based high-throughput screening(HTS^2)and a bre...Metastasis is the leading cause of human cancer deaths.Unfortunately,no approved drugs are available for antimetastatic treatment.In our study,high-throughput sequencing-based high-throughput screening(HTS^2)and a breast cancer lung metastasis(BCLM)-associated gene signature were combined to discover anti-metastatic drugs.After screening of thousands of compounds,we identified Ponatinib as a BCLM inhibitor.Ponatinib significantly inhibited the migration and mammosphere formation of breast cancer cells in vitro and blocked BCLM in multiple mouse models.Mechanistically,Ponatinib represses the expression of BCLM-associated genes mainly through the ERK/c-Jun signaling pathway by inhibiting the transcription of JUN and accelerating the degradation of c-Jun protein.Notably,JUN expression levels were positively correlated with BCLM-associated gene expression and lung metastases in breast cancer patients.Collectively,we established a novel approach for the discovery of anti-metastatic drugs,identified Ponatinib as a new drug to inhibit BCLM and revealed c-Jun as a crucial factor and potential drug target for BCLM.Our study may facilitate the therapeutic treatment of BCLM as well as other metastases.展开更多
Previous studies have suggested that thrombospondin-1(TSP-1) regulates the transforming growth factor beta 1(TGF-b1)/phosphorylated Smad2/3(p Smad2/3) pathway. Moreover, TSP-1 is closely associated with epilepsy. Howe...Previous studies have suggested that thrombospondin-1(TSP-1) regulates the transforming growth factor beta 1(TGF-b1)/phosphorylated Smad2/3(p Smad2/3) pathway. Moreover, TSP-1 is closely associated with epilepsy. However, the role of the TSP-1-regulated TGFb1/p Smad2/3 pathway in seizures remains unclear. In this study, changes in this pathway were assessed following kainic acid(KA)-induced status epilepticus(SE) in rats.The results showed that increases in the TSP-1/TGF-b1/p Smad2/3 levels spatially and temporally matched the increases in glial fibrillary acidic protein(GFAP)/chondroitin sulfate(CS56) levels following KA administration.Inhibition of TSP-1 expression by small interfering RNA or inhibition of TGF-b1 activation with a Leu-Ser-Lys-Leu peptide significantly reduced the severity of KA-induced acute seizures. These anti-seizure effects were accompanied by decreased GFAP/CS56 expression and Smad2/3 phosphorylation. Moreover, inhibiting Smad2/3 phosphorylation with ponatinib or SIS3 also significantly reduced seizure severity, alongside reducing GFAP/CS56 immunoreactivity. These results suggest that the TSP-1-regulated TGF-b1/p Smad2/3 pathway plays a key role in KA-induced SE and astrogliosis, and that inhibiting this pathway may be a potential anti-seizure strategy.展开更多
基金financial support from the Theodor Bilharz Research InstituteWarrak El-Hadar+1 种基金ImbabaGiza 12411,Egypt。
文摘Objective:To evaluate the efficacy of ponatinib plus gossypol against colorectal cancer HCT-116 and Caco-2 cells.Methods:Cells were treated with ponatinib and/or gossypol at increasing concentrations to evaluate synergistic drug interactions by combination index.Cell viability,FGF19/FGFR4,and apoptotic and autophagic cell death were studied.Results:Ponatinib(1.25-40μM)and gossypol(2.5-80μM)monotherapy inhibited HCT-116 and Caco-2 cell viability in a doseand time-dependent manner.The combination of ponatinib and gossypol at a ratio of 1 to 2 significantly decreased cell viability(P<0.05),with a>2-and>4-fold reduction in IC50,respectively,after 24 h and 48 h,as compared to the IC50 of ponatinib.Lower combined concentrations showed greater synergism(combination index<1)with a higher ponatinib dose reduction index.Moreover,ponatinib plus gossypol induced morphological changes in HCT-116and Caco-2 cells,increased beclin-1 and caspase-3,and decreased FGF19,FGFR4,Bcl-2 and p-Akt as compared to treatment with drugs alone.Conclusions:Gossypol enhances ponatinib's anticancer effects against colorectal cancer cells through antiproliferative,apoptotic,and autophagic mechanisms.This may open the way for the future use of ponatinib at lower doses with gossypol as a potentially safer targeted strategy for colorectal cancer treatment.
基金a grant from the National Natural Science Foundation of China(Grant No.81673460)fun ding from Tsinghua-Peking Joint Center for Life Sciences and Beijing Mun icipal Science&Technology Commissi on.
文摘Metastasis is the leading cause of human cancer deaths.Unfortunately,no approved drugs are available for antimetastatic treatment.In our study,high-throughput sequencing-based high-throughput screening(HTS^2)and a breast cancer lung metastasis(BCLM)-associated gene signature were combined to discover anti-metastatic drugs.After screening of thousands of compounds,we identified Ponatinib as a BCLM inhibitor.Ponatinib significantly inhibited the migration and mammosphere formation of breast cancer cells in vitro and blocked BCLM in multiple mouse models.Mechanistically,Ponatinib represses the expression of BCLM-associated genes mainly through the ERK/c-Jun signaling pathway by inhibiting the transcription of JUN and accelerating the degradation of c-Jun protein.Notably,JUN expression levels were positively correlated with BCLM-associated gene expression and lung metastases in breast cancer patients.Collectively,we established a novel approach for the discovery of anti-metastatic drugs,identified Ponatinib as a new drug to inhibit BCLM and revealed c-Jun as a crucial factor and potential drug target for BCLM.Our study may facilitate the therapeutic treatment of BCLM as well as other metastases.
基金the National Natural Science Foundation of China(81573412)the Key Research and Development Plan(2018GSF121004)the Natural Science Foundation of Shandong Province,China(ZR2014JL055).
文摘Previous studies have suggested that thrombospondin-1(TSP-1) regulates the transforming growth factor beta 1(TGF-b1)/phosphorylated Smad2/3(p Smad2/3) pathway. Moreover, TSP-1 is closely associated with epilepsy. However, the role of the TSP-1-regulated TGFb1/p Smad2/3 pathway in seizures remains unclear. In this study, changes in this pathway were assessed following kainic acid(KA)-induced status epilepticus(SE) in rats.The results showed that increases in the TSP-1/TGF-b1/p Smad2/3 levels spatially and temporally matched the increases in glial fibrillary acidic protein(GFAP)/chondroitin sulfate(CS56) levels following KA administration.Inhibition of TSP-1 expression by small interfering RNA or inhibition of TGF-b1 activation with a Leu-Ser-Lys-Leu peptide significantly reduced the severity of KA-induced acute seizures. These anti-seizure effects were accompanied by decreased GFAP/CS56 expression and Smad2/3 phosphorylation. Moreover, inhibiting Smad2/3 phosphorylation with ponatinib or SIS3 also significantly reduced seizure severity, alongside reducing GFAP/CS56 immunoreactivity. These results suggest that the TSP-1-regulated TGF-b1/p Smad2/3 pathway plays a key role in KA-induced SE and astrogliosis, and that inhibiting this pathway may be a potential anti-seizure strategy.
