To study the relationship between angiogenesis and the expression of bFGF andFGFR-1 in lung cancer. Methods: The specimens of 56 patients with lung cancer treated with surgerywere collected. Anti-Von Willebrand factor...To study the relationship between angiogenesis and the expression of bFGF andFGFR-1 in lung cancer. Methods: The specimens of 56 patients with lung cancer treated with surgerywere collected. Anti-Von Willebrand factor antibody was used to measure microvascular density (MVD)by means of SABC immunohistochemical technique, and antibody to basic fibroblast growth factor(bFGF) and its receptor (FGFR-1) to detect the expression of these three proteins in the tumortissues. The survival time was compared between low MVD and high MVD groups by the Kaplan-Meiermethod. Results: (1) The expression of MVD showed no significant difference in some clinicalcharacteristics, including sex, age, T stage, M stage and pathologic type, but significantdifference in N stage (P 【 0.01) and clinical stage (P 【 0.05). (2) Survival analysis showed thathigh MVD group was associated with a risk of death (P 【 0.01). (3) The expression of bFGF and FGFR-1were both related to lymphatic metastasis and clinical staging (P 【 0.05). (4) Significantdifference was seen between low MVD and high MVD groups in the bFGF expression in lung cancer (P 【0.01), whereas no correlation in FGFR-1. (5) High co-expression of bFGF and FGFR-1 was consistent intumor cells. Conclusion: (1) MVD is a good prognostic factor for patients of lung cancer, and thesame as bFGF. (2) The angiogenesis may be induced after bFGF binding to FGFR-1.展开更多
Artemisinin and its derivatives(ARTs) were reported to display heme-dependent antitumor activity. On the other hand, histone deacetylase inhibitors(HDACi) were known to be able to promote heme synthesis in erythroid c...Artemisinin and its derivatives(ARTs) were reported to display heme-dependent antitumor activity. On the other hand, histone deacetylase inhibitors(HDACi) were known to be able to promote heme synthesis in erythroid cells. Nevertheless, the effect of HDACi on heme homeostasis in nonerythrocytes remains unknown. We envisioned that the combination of HDACi and artesunate(ARS)might have synergistic antitumor activity through modulating heme synthesis. In vitro studies revealed that combination of ARS and HDACi exerted synergistic tumor inhibition by inducing cell death. Moreover, this combination exhibited more effective antitumor activity than either ARS or HDACi monotherapy in xenograft models without apparent toxicity. Importantly, mechanistic studies revealed that HDACi coordinated with ARS to increase 5-aminolevulinate synthase(ALAS1) expression, and subsequent heme production, leading to enhanced cytotoxicity of ARS. Notably, knocking down ALAS1 significantly blunted the synergistic effect of ARS and HDACi on tumor inhibition, indicating a critical role of ALAS1 upregulation in mediating ARS cytotoxicity. Collectively, our study revealed the mechanism of synergistic antitumor action of ARS and HDACi. This finding indicates that modulation of heme synthesis pathway by the combination based on ARTs and other heme synthesis modulators represents a promising therapeutic approach to solid tumors.展开更多
A series of novel, cycloalkyl-modified pazopanib analogs 2 and 3 were designed and synthesized. Their kinase modulatory effects on FGFR-1, VEGFR-2, PDGFR-β and c-KIT were evaluated by the caliper mobility shift assay...A series of novel, cycloalkyl-modified pazopanib analogs 2 and 3 were designed and synthesized. Their kinase modulatory effects on FGFR-1, VEGFR-2, PDGFR-β and c-KIT were evaluated by the caliper mobility shift assay. Introduction of cycloalkyl into the pyrimidine linker of pazopanib almost abolished the four kinases inhibitory potency of compounds 2 and 3, but surprisingly, resulted in good activation effects on FGFR-1. Compounds 3d and 3g showed double-digit, nanomolar, selective activation effects on FGFR-1, and could be classified as first-generation small molecular activators of FGFR-1 kinase.展开更多
文摘To study the relationship between angiogenesis and the expression of bFGF andFGFR-1 in lung cancer. Methods: The specimens of 56 patients with lung cancer treated with surgerywere collected. Anti-Von Willebrand factor antibody was used to measure microvascular density (MVD)by means of SABC immunohistochemical technique, and antibody to basic fibroblast growth factor(bFGF) and its receptor (FGFR-1) to detect the expression of these three proteins in the tumortissues. The survival time was compared between low MVD and high MVD groups by the Kaplan-Meiermethod. Results: (1) The expression of MVD showed no significant difference in some clinicalcharacteristics, including sex, age, T stage, M stage and pathologic type, but significantdifference in N stage (P 【 0.01) and clinical stage (P 【 0.05). (2) Survival analysis showed thathigh MVD group was associated with a risk of death (P 【 0.01). (3) The expression of bFGF and FGFR-1were both related to lymphatic metastasis and clinical staging (P 【 0.05). (4) Significantdifference was seen between low MVD and high MVD groups in the bFGF expression in lung cancer (P 【0.01), whereas no correlation in FGFR-1. (5) High co-expression of bFGF and FGFR-1 was consistent intumor cells. Conclusion: (1) MVD is a good prognostic factor for patients of lung cancer, and thesame as bFGF. (2) The angiogenesis may be induced after bFGF binding to FGFR-1.
基金supported by grants from the National Natural Science Foundation of China(grants 31501182,81573299 and81730094)the “111 Project” from the Ministry of Education of China to Hongbin Sun+1 种基金the State Administration of Foreign Experts Affairs of China,China(No.111-2-07)Fundamental Research Funds for the Central Universities,China(2632017ZD05)
文摘Artemisinin and its derivatives(ARTs) were reported to display heme-dependent antitumor activity. On the other hand, histone deacetylase inhibitors(HDACi) were known to be able to promote heme synthesis in erythroid cells. Nevertheless, the effect of HDACi on heme homeostasis in nonerythrocytes remains unknown. We envisioned that the combination of HDACi and artesunate(ARS)might have synergistic antitumor activity through modulating heme synthesis. In vitro studies revealed that combination of ARS and HDACi exerted synergistic tumor inhibition by inducing cell death. Moreover, this combination exhibited more effective antitumor activity than either ARS or HDACi monotherapy in xenograft models without apparent toxicity. Importantly, mechanistic studies revealed that HDACi coordinated with ARS to increase 5-aminolevulinate synthase(ALAS1) expression, and subsequent heme production, leading to enhanced cytotoxicity of ARS. Notably, knocking down ALAS1 significantly blunted the synergistic effect of ARS and HDACi on tumor inhibition, indicating a critical role of ALAS1 upregulation in mediating ARS cytotoxicity. Collectively, our study revealed the mechanism of synergistic antitumor action of ARS and HDACi. This finding indicates that modulation of heme synthesis pathway by the combination based on ARTs and other heme synthesis modulators represents a promising therapeutic approach to solid tumors.
基金provided by the National Natural Science Foundation of China(Nos.21222211,21372001,91313303)the Program for New Century Excellent Talents in University(No.NCET-12-0853)the Fundamental Research Funds for the Central Universities are gratefully acknowledged
文摘A series of novel, cycloalkyl-modified pazopanib analogs 2 and 3 were designed and synthesized. Their kinase modulatory effects on FGFR-1, VEGFR-2, PDGFR-β and c-KIT were evaluated by the caliper mobility shift assay. Introduction of cycloalkyl into the pyrimidine linker of pazopanib almost abolished the four kinases inhibitory potency of compounds 2 and 3, but surprisingly, resulted in good activation effects on FGFR-1. Compounds 3d and 3g showed double-digit, nanomolar, selective activation effects on FGFR-1, and could be classified as first-generation small molecular activators of FGFR-1 kinase.
