Background:The increasing incidence of cancers and infectious diseases worldwide presents a significant public health challenge that requires immediate intervention.Our strategy to tackle this issue involves the devel...Background:The increasing incidence of cancers and infectious diseases worldwide presents a significant public health challenge that requires immediate intervention.Our strategy to tackle this issue involves the development of pharmaceutical formulations that combine phytopolyphenols(P),targeted drugs(T),and metal ions(M),collectively referred to as PTM regimens.The diverse pharmacological properties of PTM regimens are hypothesized to effectively reduce the risk factors associated with both cancers and infectious diseases.Methods:The effects of the pharmaceutical agents on the proliferation of cultured cancer cells and pathogens were assessed after 72 h and 48 h,respectively,using the MTT(3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide)assay and optical density at 600 nm(OD600).The synergistic effects of drug combinations were evaluated by combination index(CI),where CI<1 indicates synergism,CI=1 indicates addition,and CI>1 indicates antagonism.Efficacy index(EI)was also calculated.Assays of efflux pump ATPase activities were conducted using a colorimetric method.Results:This study evaluated the anticancer and antibacterial efficacy of PTM regimens that included phytopolyphenols(specifically curcumin(C)and green tea polyphenols(G)),repurposed drugs(memantine(Mem),thioridazine(TRZ),cisplatin(Cis),and 5-fluorouracil(5FU)),and ZnSO_(4)(Zn)across three cultured cancer cell lines and four cultured pathogens.The most effective regimens,GC·Mem·Zn and GC·TRZ·Zn,significantly enhanced the anticancer efficacy(EI)of cisplatin across the three cancer lines(OECM-1,A549 and DLD-1)by 7,11 and 21;7,9,and 17 fold,respectively,while the enhancements for 5-fluorouracil were 5,6 and 12;5,5 and 9 fold,respectively.Furthermore,these PTM regimens demonstrated substantial synergistic inhibition of Na^(+)-K^(+)-Mg^(2+)-ATPase and Mg^(2+)-ATPase in the cultured cancer cells,as well as a reduction in biofilm formation by the four cultured pathogens,suggesting their potential to address the challenges of multidrug resistance in cancers and infectious diseases.Conclusion:Given that all drugs incorporated in the PTM regimens have been clinically validated for safety and efficacy,particularly regarding their synergistic selective anticancer efficacy,inhibition of efflux pump ATPase,and antibiofilm formation of pathogens,these regimens may offer a promising therapeutic strategy to alleviate the severe side effects and drug resistance typically associated with chemotherapeutic agents.Further preclinical and clinical investigations are warranted.展开更多
AIM: To explore both the in vitro and in vivo effects of denbinobin against colon cancer cells and clarify its underlying signal pathways. METHODS: We used COLO 205 cancer cell lines and nude mice xenograft model to s...AIM: To explore both the in vitro and in vivo effects of denbinobin against colon cancer cells and clarify its underlying signal pathways. METHODS: We used COLO 205 cancer cell lines and nude mice xenograft model to study the in vitro and in vivo anti-cancer effects of denbinobin. RESULTS: Denbinobin at concentration of 10-20 μmol/L dose-dependently suppressed COLO 205 cell proliferation by MTT test. Flow cytometry analysis and DNA fragmentation assay revealed that 10-20 μmol/L denbinobin treatment induced COLO 205 cells apoptosis. Western blot analysis showed that caspases 3,8,9 and Bid protein were activated by denbinobin treatment to COLO 205 cells accompanied with cytochrome c and apoptosis-inducing factor (AIF) translocation. Pretreatment of MEK 1 inhibitor (U10126), but not p38 inhibitor (SB203580) and JNK inhibitor (SP600125), reversed denbinobin-induced caspase 8, 9 and Bid activation in COLO 205 cells suggesting that extracellular signal-regulated kinase were involved in the denbinobin-induced apoptosis in COLO 205 cells. Significant regression of tumor up to 68% was further demonstrated in vivo by treating nude mice bearing COLO 205 tumor xenografts with denbinobin 50 mg/kg intraperitoneally. CONCLUSION: Our findings suggest that denbinobin could inhibit colon cancer growth both in vitro and in vivo. Activation of extrinsic and intrinsic apoptotic pathways and AIF were involved in the denbinobin-induced COLO 205 cell apoptosis.展开更多
AIM: Fatty acid-CoA ligase 4 (FACL4) is an arachidonatepreferring enzyme which has been shown to be up-regulated in human colon cancer tissues and implicated in the colon tumorigenesis. The purpose of this study was t...AIM: Fatty acid-CoA ligase 4 (FACL4) is an arachidonatepreferring enzyme which has been shown to be up-regulated in human colon cancer tissues and implicated in the colon tumorigenesis. The purpose of this study was to investigatethe role of FACL4 in the human hepatocellular carcinoma (HCC) tumorigenesis and the specific signal pathways involved in this process.METHODS: We investigated the expression and regulation of FACL4 in HCC, adjacent non-tumorous liver tissues, and cell lines.RESULTS: In HCC patients, we demonstrated that FACL4 gene expression was markedly elevated in the cancerous tissues than in the adjacent non-cancerous liver tissues.In addition, several human hepatoma cell lines, including Hep3B and HepG2, expressed high levels of FACL4. Stable overex-pression of FACL4 knockdown plasmids (small interfering RNA, siRNA) to Hep3B cells significantly decreased FACL4 expression and subsequently limited the cell proliferation. Treatment of Hep3B cells with 8bromo-cAMP and SB203508 (p38 MAPK inhibitor) significantly suppressed the FACL4 expression. CONCLUSION: FACL4 is involved in the HCC tumorigenesis and both cAMP and p38 MAPK pathways are associated with the regulation of FACL4 in HCC.展开更多
文摘Background:The increasing incidence of cancers and infectious diseases worldwide presents a significant public health challenge that requires immediate intervention.Our strategy to tackle this issue involves the development of pharmaceutical formulations that combine phytopolyphenols(P),targeted drugs(T),and metal ions(M),collectively referred to as PTM regimens.The diverse pharmacological properties of PTM regimens are hypothesized to effectively reduce the risk factors associated with both cancers and infectious diseases.Methods:The effects of the pharmaceutical agents on the proliferation of cultured cancer cells and pathogens were assessed after 72 h and 48 h,respectively,using the MTT(3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide)assay and optical density at 600 nm(OD600).The synergistic effects of drug combinations were evaluated by combination index(CI),where CI<1 indicates synergism,CI=1 indicates addition,and CI>1 indicates antagonism.Efficacy index(EI)was also calculated.Assays of efflux pump ATPase activities were conducted using a colorimetric method.Results:This study evaluated the anticancer and antibacterial efficacy of PTM regimens that included phytopolyphenols(specifically curcumin(C)and green tea polyphenols(G)),repurposed drugs(memantine(Mem),thioridazine(TRZ),cisplatin(Cis),and 5-fluorouracil(5FU)),and ZnSO_(4)(Zn)across three cultured cancer cell lines and four cultured pathogens.The most effective regimens,GC·Mem·Zn and GC·TRZ·Zn,significantly enhanced the anticancer efficacy(EI)of cisplatin across the three cancer lines(OECM-1,A549 and DLD-1)by 7,11 and 21;7,9,and 17 fold,respectively,while the enhancements for 5-fluorouracil were 5,6 and 12;5,5 and 9 fold,respectively.Furthermore,these PTM regimens demonstrated substantial synergistic inhibition of Na^(+)-K^(+)-Mg^(2+)-ATPase and Mg^(2+)-ATPase in the cultured cancer cells,as well as a reduction in biofilm formation by the four cultured pathogens,suggesting their potential to address the challenges of multidrug resistance in cancers and infectious diseases.Conclusion:Given that all drugs incorporated in the PTM regimens have been clinically validated for safety and efficacy,particularly regarding their synergistic selective anticancer efficacy,inhibition of efflux pump ATPase,and antibiofilm formation of pathogens,these regimens may offer a promising therapeutic strategy to alleviate the severe side effects and drug resistance typically associated with chemotherapeutic agents.Further preclinical and clinical investigations are warranted.
基金Supported by the Shin Kong Wu Ho-Su Memorial Hospital (SKH-TMU-93-16)the Chi Mei Medical Center (93CM-TMU-09)
文摘AIM: To explore both the in vitro and in vivo effects of denbinobin against colon cancer cells and clarify its underlying signal pathways. METHODS: We used COLO 205 cancer cell lines and nude mice xenograft model to study the in vitro and in vivo anti-cancer effects of denbinobin. RESULTS: Denbinobin at concentration of 10-20 μmol/L dose-dependently suppressed COLO 205 cell proliferation by MTT test. Flow cytometry analysis and DNA fragmentation assay revealed that 10-20 μmol/L denbinobin treatment induced COLO 205 cells apoptosis. Western blot analysis showed that caspases 3,8,9 and Bid protein were activated by denbinobin treatment to COLO 205 cells accompanied with cytochrome c and apoptosis-inducing factor (AIF) translocation. Pretreatment of MEK 1 inhibitor (U10126), but not p38 inhibitor (SB203580) and JNK inhibitor (SP600125), reversed denbinobin-induced caspase 8, 9 and Bid activation in COLO 205 cells suggesting that extracellular signal-regulated kinase were involved in the denbinobin-induced apoptosis in COLO 205 cells. Significant regression of tumor up to 68% was further demonstrated in vivo by treating nude mice bearing COLO 205 tumor xenografts with denbinobin 50 mg/kg intraperitoneally. CONCLUSION: Our findings suggest that denbinobin could inhibit colon cancer growth both in vitro and in vivo. Activation of extrinsic and intrinsic apoptotic pathways and AIF were involved in the denbinobin-induced COLO 205 cell apoptosis.
基金Supported by the National Science Council of Taiwan Chna(NSC 91-2320-B-038-030- and 92-2320-B-038-051-)Taipei Medical University (TMU 91-Y05-A138)
文摘AIM: Fatty acid-CoA ligase 4 (FACL4) is an arachidonatepreferring enzyme which has been shown to be up-regulated in human colon cancer tissues and implicated in the colon tumorigenesis. The purpose of this study was to investigatethe role of FACL4 in the human hepatocellular carcinoma (HCC) tumorigenesis and the specific signal pathways involved in this process.METHODS: We investigated the expression and regulation of FACL4 in HCC, adjacent non-tumorous liver tissues, and cell lines.RESULTS: In HCC patients, we demonstrated that FACL4 gene expression was markedly elevated in the cancerous tissues than in the adjacent non-cancerous liver tissues.In addition, several human hepatoma cell lines, including Hep3B and HepG2, expressed high levels of FACL4. Stable overex-pression of FACL4 knockdown plasmids (small interfering RNA, siRNA) to Hep3B cells significantly decreased FACL4 expression and subsequently limited the cell proliferation. Treatment of Hep3B cells with 8bromo-cAMP and SB203508 (p38 MAPK inhibitor) significantly suppressed the FACL4 expression. CONCLUSION: FACL4 is involved in the HCC tumorigenesis and both cAMP and p38 MAPK pathways are associated with the regulation of FACL4 in HCC.
