| Summary: | 博士 === 國立臺灣大學 === 藥理學研究所 === 102 === Angiogenesis, which is the process of formation of new blood vessels from pre-existing ones, takes place throughout physiological development, tissue repair, and reproduction. In pathological conditions, angiogenesis is also essential for tumor growth and progression to ensure that more oxygen and nutrients are delivered from the host’s vascular system. Therefore, angiogenesis is a promising target for anticancer treatments. In this thesis, we focused on the discovery of potential novel antiangiogenic agents, and further investigated the mechanism of these agents.
In the first part, we investigated the traditional Chinese medicine component dehydrocostuslactone (DHC) isolated from Saussurea costus (Falc.) Lipschitz, which has been shown to have anti-cancer activity. DHC has an anti-angiogenic effect in the matrigel-plug nude mice model and an inhibitory effect on HUVEC proliferation and capillary-like tube formation in vitro. With respect to the molecular mechanisms underlying the DHC-induced cyclin D1 down-regulation, we demonstrated that DHC significantly inhibited Akt expression, resulting in the suppression of GSK-3b phosphorylation and mTOR expression. Furthermore, the degradation of cyclin D1 and the abrogation of tube formation induced by DHC were significantly reversed by constitutively active myristoylated (myr)-Akt. And the co-treatment with LiCl and DHC significantly reversed the growth inhibition induced by DHC.
Tissue inhibitors of metalloproteinases 3 (TIMP3) were originally characterized as inhibitors of matrix metalloproteinases (MMPs), acting as potent antiangiogenic proteins. In the second part, we demonstrated that the arylsulfonamide derivative MPT0G013 has potent antiangiogenic activities in vitro and in vivo via inducing TIMP3 expression. Treatments with MPT0G013 significantly inhibited endothelial cell functions, such as cell proliferation, migration, and tube formation. Subsequent microarray analysis showed significant induction of TIMP3 gene expression by MPT0G013, and siRNA-mediated blockage of TIMP3 up-regulation abrogated the antiangiogenic activities of MPT0G013 and prevented inhibition of p-AKT and p-ERK proteins. Importantly, MPT0G013 exhibited antiangiogenic activities in in vivo Matrigel plug assays, inhibited tumor growth and up-regulated TIMP3 and p21 proteins in HCT116 mouse xenograft models.
MPT0B271, an orally active microtubule-targeting agent, is a completely synthetic compound that possesses potent anticancer effects in vitro and in vivo. MPT0B271 caused depolymerization of tubulin at both molecular and cellular levels and reduced cell growth and viability at nanomolar concentrations in numerous cancer cell lines, including a multidrug-resistant cancer cell line NCI/ADR-RES. Further studies indicated that MPT0B271 is not a substrate of p-gp, as determined by flow cytometric analysis of Rh-123 dye efflux and the calcein AM assay. MPT0B271 also caused G2/M cell-cycle arrest, accompanied by induction of cell apoptosis. We demonstrated that MPT0B271 in combination with erlotinib significantly inhibits the growth of the NSCLC A549 cells as compared with erlotinib treatment alone, both in vitro and in vivo. These findings identify MPT0B271 as a promising new tubulin-binding compound for the treatment of various cancers.
Taken together, the present studies have highlighted the potential application of DHC and MPT0G013 in angiogenesis-related diseases, such as cancer. And the anti-tumor agent MPT0B271 may foster novel therapeutic strategies for various cancer cell lines.
|
|---|
