探討雙高石膽酸衍生物對於唾液酸轉移酶及癌細胞轉移的影響
No Thumbnail Available
Date
2019
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
在台灣，癌症為十大死因之首，其中癌細胞轉移為九成癌症病人之死因。癌細胞表面具有過度表現的唾液酸是細胞癌化的重要指標，此現象不僅會促進癌細胞的生長，亦可增加其侵犯周邊組織與轉移之能力。已有實驗證實，藉由調控唾液酸轉移酶能影響細胞表面之唾液酸表現。因此，抑制唾液酸轉移酶的活性會是一個有潛力的癌症轉移治療方式。
我們合成雙高石膽酸衍生物HZF01-04，並進行初步生物試驗的研究與探討。HZF01-04具有極高的選擇性唾液酸轉移酶抑制能力，針對ST6Gal I有良好的抑制效果，其IC50數值介於7.8-12.2 μM之間。此外，HZF01-04對於人類三陰性乳癌細胞株MDA-MB-231的轉移能力具有抑制效果，其IC50數值之範圍介於7.5-10 μM之間。進一步的生物活性測試正在進行中，包括物化性質與動物實驗。
此研究結果有助於選擇性唾液酸轉移酶抑制劑的開發，希望能應用於N-醣鏈過度唾液酸化的癌症病人之治療。
Cancer is the major cause of death and metastasis is the greatest contributor to cancer deaths. Tumor cells display elevated expression of sialic acid on membranes, which promote cancer cell metastasis and progression. Aberrant sialylation is correlated with poor patient prognosis. Therefore, interfering hypersialylation through inhibition of sialytransferase activity may be a therapeutic target to metastatic cancer. In this investigation, we synthesized a series of bishomolithocholic acid derivatives HZF01-04 with various length linkers. HZF01-04 demonstrated significant inhibitory selectivity toward N-glycan sialyltransferase, β-galactoside α-2,6-sialyltransferase (ST6Gal I). The selectivity ratio of N-glycan vs O-glycan is over 80-fold. The findings show that HZF01-04 suppress serum-induced cancer cell migration in a dose dependent manner. Further studies for their mechanism of action and animal model are in progress. These efforts pave the way for the development of selective sialyltransferase inhibitors as effective anti-metastatic agents for the treatment of patients with aberrant overexpression of N-glycan sialylation.
Cancer is the major cause of death and metastasis is the greatest contributor to cancer deaths. Tumor cells display elevated expression of sialic acid on membranes, which promote cancer cell metastasis and progression. Aberrant sialylation is correlated with poor patient prognosis. Therefore, interfering hypersialylation through inhibition of sialytransferase activity may be a therapeutic target to metastatic cancer. In this investigation, we synthesized a series of bishomolithocholic acid derivatives HZF01-04 with various length linkers. HZF01-04 demonstrated significant inhibitory selectivity toward N-glycan sialyltransferase, β-galactoside α-2,6-sialyltransferase (ST6Gal I). The selectivity ratio of N-glycan vs O-glycan is over 80-fold. The findings show that HZF01-04 suppress serum-induced cancer cell migration in a dose dependent manner. Further studies for their mechanism of action and animal model are in progress. These efforts pave the way for the development of selective sialyltransferase inhibitors as effective anti-metastatic agents for the treatment of patients with aberrant overexpression of N-glycan sialylation.
Description
Keywords
唾液酸, 唾液酸轉移酶, 癌症轉移, 雙高石膽酸, sialic acid, sialyltransferase, metastasis, bishomolithocholic acid