Mechanism for Anti-angiogenic Activity of Wondonin Analogues : Wondonin 유도체의 혈관신생 억제 작용기전 연구
- 약학대학 약학과
- Issue Date
- 서울대학교 대학원
- Angiogenesis ; Wondonin analogues ; VEGF signaling ; Human umbilical vein endothelial cells (HUVEC) ; mouse embryonic stem cell (mES)/embryonic body (EB) ; Zebrafish
- 학위논문 (박사)-- 서울대학교 대학원 약학대학 약학과, 2017. 8. 이상국.
- Angiogenesis is the process which is essential in development of the adult or the fetus. But pathologic angiogenesis (excessive or insufficient) is becoming the cause of various disease which like cancer, age-related macular degeneration (AMD), diabetic retinopathy and cardio vascular disease etc. Thus, many research progress about treatment of diseases which is caused by with unusual blood vessel formation.
Next, synthesized derivatives which base on the wondonin from marine organism. So, excellent anti-angiogenic effect was investigated by these wondonin analogues.
In this research tried to anti-angiogenic effect and mechanism of wondonin analogues. Therefore, this study searching for the derivative which it doesnt have toxicity in cell and effectively suppresses angiogenesis.
First, activities and SI values of analogues were compared with those of wondonin.
And then, analogues were sorted through tube formation assay which is index of new blood vessel formation and cytotoxicity assay.
Among the wondonin analogues, ST-XII-145 was effectively suppressed PI3K/AKT/eNOS, FAK and p38 protein expression in VEGF-induced condition and hypoxic condition. The based on like this in-vitro result and then performed mouse aorta ring assay (ex-vivo) and zebrafish angiogenesis assay (in-vivo). In this result, it had able to observe an angiogenesis suppression ability.
To investigation of suppression of blood vessel formation in generating process, used mouse embryonic stem cell as differentiate endothelial cells. And then, it used immunocytochemistry methods which anti-angiogenic activity of differentiated endothelial cell and it confirms. After, attempted finding to new analogues that improved activity to stand on the basis of ST-XII-145.
In order to lower the cytotoxicity and raise activity, led to analogues which are various it synthesized by structural change. Selected ST2-VI-66 among the synthesized analogues because SI value and activity are highest. When investigated the molecular targets of anti-angiogenic activity of ST2-VI-66, it suppressed PI3K-AKT-eNOS and FAK signaling pathway.
Furthermore, in order to secure another applicability of diseases treatment which leads angiogenesis suppression the diabetic retinopathy disease model in zebrafish it applied. As a result, ST2-VI-66 effectively suppressed vessel of expanded by high-glucose.
Herein, wondonin derivatives suppressed VEGF signal transduction systems and it presents the possibility as the candidate compound it will be able to overcome the diseases which occur with the angiogenesis.