CSC-3436 Induces Apoptosis Human Umbilical Vein Endothelial Cells via p53-mediated Death Receptor Up-regulation

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.11"-ωC-3436 Induces Apopω鈍。fHuman Umbilical Vein

Endothelial Cells via p53-mediated Death Receptor

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!J二也I且 LIU t，SHENG-CHU KUO', TZONG-DER WAY' ('Grad. 1nst. of

PharmaceuticaI Chemistry, China MedicaI U叫眠，Taiwan，'Dept. of Biologiωl Science and Technology, China Medical Univ., Taiwan)

CSC-3436 is a 2-phenyl-1,8-naphthyridin-4-one (2-PN) derivative, was synthesized and evaIuated as an effective antitumor agent. However, its role in tumor angiogenesis is unclear.τbis study investigated the effects of

CSC-3436 and the mechanisms by which exerts its antiangiogenic. We found 出at

CSC-3436 significantly inhibited microvesselformation. CSC-3436 inhibited proliferation of human umbilicaI vein endotheliaI cells (HUVEC) by induction of apoptotic cell death in a concentration-dependent manner. CSC-3436 also suppressed HUVEC migration and capillary-like tube formation. We were able to correlate CSC-3436 induced apoptosis in HUVEC with the cleavage of procaspase-3 and 品， as well as with the cleavage of poly (ADP-ribose) polymerase by Western blotting ass那 Such sensitization was achieved through up-regulation of death receptor(DR). CSC-3436 was aIso capable of increasing the expression level of p53. The results of this study indicated 出at

CSC-3436 exhibited vascular targeting activity associated wi出 theinduction of DR-mediated endothelial cell apoptosis through p53 up-regulation, which suggests its potential as an antivascular and antitumor therapeutic agent. Keywords: Angiogenesis, Death Receptor

Keywords: aquaporin, Angiogenesis

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多 y 卜 |ζ 副主志直接的 U 二 Y 阻害鑫仿血管新生抑制老介 iJ T.:肝凳癌抑制劫果

相原洋祐、吉治仁志、野口隆一、波崎正、鍛;台孝祐、福井博(奈良果

立區科大字第 3 內科)

We previously reported that the renin-angiotensin system(RAS) plays a pivotal role in hepatocarcinogenesis, and clinically used several RAS inhibitory agents suppressed it via angiogene剖sinhibition τbe aim of our current study was to elucidate the effect of a recently developed direct renin inhibitor (DRI),AIiskiren, in the rat hepatocarcinogenesis model. Hepatocarcinogenesis model was induced in maIe F344 rats by the choline-deficient l.raminoacid-defined diet for 12 weeks.τbe hep咀tocarcinogenesis was examined with clinically comparable low doses of D眩，especially in conjunction with neovascularization. The glutathione-S-甘ansferaseplacental form-positive pre-neoplastic lesions were markedly attenuated by DRI aIong with the suppression of neovascularization and VEGF in adose-dependent manner. Our in vitro study showed that renin significantly augmented the in-vitroangiogenesis, whereas, interestingly, DRI did not inhibit the renin-induced EC proliferation even at high dose. Since DRI is widely used in the clinical practice without serious side effects, DRI could represent a potentiaI

news甘ategyagainst hepatocarcinogenesis in the future.

Keywo昕ds:Angiogenesis, Hepato臼 llularcarcinoma

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基金旦旦k立五星ji， Hitoshi Yoshiji, Ryuichi Noguchi, Yousuke Aihara, Tadashi

N缸nis位ci ，Hiroshi Fukui (Third Dept. of InternaI Med., Nara Medical Univ.)

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立區科大字第 3 內科)

1ron overload plays an important role in hepatocarcinogenesis via accumulation of reactive oxygen species (ROS) in the liver. Moreover, ROS is known as a key mediator promoting tumor angiogenesisτbis study was designed to elucidate the effect of deferasirox (DS劫，a newly developed oral iron chelator on hepatocarcinogenesis in conjunction with ROS and angiogenesis. To induce hepatocarcinogenesis, F344 rats were fed a choline-deficient l.ramino acid-defined (CDAA) diet for 12 weeks. DSX at clinically comparable low dose suppressed CDAA-induced hepatocarcinogenesis in

pallarelwi由 thesuppression of oxidative DNA damage and lipid peroxidation.

AdditionaIly, these inhibitory effects occurred almost concurrently with the attenuation of neovascularization and vascular endothelial growth factor

(VEGF) expression in the liver. These results indicate that DSX inhibits

hepatocarcinogenesis through antioxidative and antiangiogenic effects. Since DSX is widely used in clinicaI practic皂，this agent may represent a potential new strategy against hepatβcarcinogenesis wi出 multiplesteps including anti-angiogenesis in 出enear future

Keyword: Reactive oxygen species

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~tivated b也且 Tahara'且，Yumi Kinugasa', Takahiro Matsui', AIcihiro Kawauch戶，

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~or of Tie~ Univ., 'Dept. of Urology, Kyoto PrefecturaI Univ. of Med.)

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米田國 5叩，20(Thu) 17:20 -18:10 Tumor angiogenesis (2)

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metastasÍlSOO: Noritaka Ohga (Dept. ofVascular Biol., Dental Med., Hokk剖do ~sized to 仕 Univ.)

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tected in Hive:The objective of this study was to investigate the critical role of

ter gene asjiÌn-3 凶 vasculogenicmimicry formation of GAC, and then reveal the

組onof VASlar mechanisms involved.

CC ceJls, E~s: 甘1esilencing of AQP3 (with lentiviral shRNA) in human GAC

'e examinece SGC7901 was performed to investigate the role of AQP3 in VM by ing the change of VM formation and the expression of VM related

!) was invenA Three-dimensional culture model was utilized for experiments in VASH23'U

led E-cadheì:The silence of AQP3 or inhibition of PI3K/ AKT signal pathway in ;ion and d~lled to a signi且cantdecrease in VM formation; Down-regulation of

2ted genes such as vascular endothelial (VE)-cadherin, membrane

target vama甘ixmetalloproteinase (MT1-MMP), and ma甘ixmetalloproteinas

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sions:The results of 出sstudy reveaI AQP3 as an important regulator ~C adenocarcinoma VM by mediating the expression of VE-cadherin, ~Mp， and MMP-2 through PI3K/ AKT signal pathway in SGC7901

rmore, AQP3 and related molecular pathways may represent a

erapeutic target for the inhibition of GAC angiogenesis and tumor

ment by cutting down the blood supply rrom VM.