中科院上海生科院營養(yǎng)所,、藥物研究所，以及美國梅奧臨床醫(yī)學院等處的研究人員發(fā)現(xiàn)了抗癌小分子藥物新型鐵螯合劑TSC24（thiosemicarbazone-24）的作用新機制,，這將為肝癌的預防和治療提供新思路,。這一研究成果發(fā)表在國際學術(shù)期刊Clinical Cancer Research上,。
肝癌是嚴重影響人類健康的疾病,，居世界腫瘤死因的第三位,，開發(fā)以肝癌中異常高表達分子為靶點的高特異性抗癌藥物具有重要的臨床意義,。鐵是人體必需的微量元素之一,，同時鐵的過量蓄積是肝癌發(fā)生發(fā)展的重要危險因素之一,，提示鐵可以作為一種新的癌癥治療靶點。
營養(yǎng)所王慧組巴乾等研究人員在細胞及動物水平對新型鐵螯合劑TSC24（thiosemicarbazone-24）的鐵螯合效率和抗肝癌活性及其分子機理進行了深入探討,，發(fā)現(xiàn)TSC24可螯合鐵、抑制鐵吸收并打破細胞內(nèi)鐵的代謝平衡,，造成細胞缺鐵,，同時誘導肝癌細胞G2/M 周期阻滯，通過Caspase途徑誘導細胞凋亡,，從而發(fā)揮抗肝癌活性,。
這項研究得到了國家科技部、國家自然科學基金委,、中國科學院和上海市科委的資助,，研究成果將為肝癌的預防和治療提供新思路。(生物谷Bioon.com)
doi:10.1158/1078-0432.CCR-10-3099
PMC:
PMID:
Iron deprivation suppresses hepatocellular carcinoma growth in experimental studies
Qian Ba, Miao Hao, He Huang, Junmei Hou, Shichao Ge, Zhuzhen Zhang, Jun Yin, Ruiai Chu, Liang Hua Jiang, Fudi Wang, Kaixian Chen, Hong Liu, and Hui Wang
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death and iron overload is a significant risk factor in the development of HCC. In this study we investigated the potential application of depriving iron by a novel iron chelator, thiosemicarbazone-24 (TSC24), in HCC treatment. Experimental Design:Two HCC cell lines and HFE knockout (HFE-/-) mice were used to determine iron chelation efficiency of TSC24. The anticancer effects of TSC24 on HCC were analyzed in vitro and in athymic xenograft mouse models. Results:Treatment with TSC24 significantly decreased the cellular iron concentration in hepatoma cells and the serum iron concentration in HFE-/- mice, by blocking iron uptake and interfering with normal regulation of iron levels. Moreover, the viability of HCC cell lines was reduced by TSC24. Confirming the mechanism of the agent, this decrease in viability could be partially rescued by addition of exogenous iron. TSC24 also suppressed tumor growth in athymic mice bearing human HCC xenografts in a concentration dependent manner without apparent toxicity in parallel with a decrease in the serum iron level. Further studies revealed that TSC24 efficiently triggered cell cycle arrest and apoptosis in Hep3B and HepG2 cell lines. Conclusions:TSC24 is a potent iron chelator that suppresses human HCC tumor growth by disrupting iron homeostasis, reducing available iron and triggering cell cycle arrest and apoptosis, without apparent host toxicity at effective doses. Thus, TSC24 shows great potential for the treatment of HCC.
