| 摘要: | 硒代胱胺酸（Selenocysteine, SeC）是一種含有重要微量營養素硒（Selenium, Se） 的化合物，近年來陸續有研究指出硒代胱胺酸具有抗癌的潛力。SeC對多種癌細胞表現出選擇性毒性（selective toxicity），主要透過調控活性氧化物（Reactive oxygen species, ROS）引發細胞凋亡機制，特別是具有較高抗藥性的癌細胞，對硒化物更敏感，但在正常細胞中則表現出較低的毒性。然而，硒代胱胺酸作用於癌細胞的機制尚不明確，臨床實驗的結果也不具一致性，推論與劑量、硒化物種類和遺傳因子有關。此外許多癌症類型，例如大腸直腸癌（colorectal cancer, CRC）、其遺傳複雜性和異質性也使其治療更加複雜與挑戰。
為了釐清硒代胱胺酸的機制，我們根據文獻以果蠅建立帶有致癌基因Ras，及抑癌基因PTEN, APC, P53之單一及多基因變異組合的大腸癌模型，進行高通量全動物模型（whole animal model）研究。果蠅大腸癌模型表現出易於觀察和可量化的腫瘤特徵，包括較高的早期死亡率、成蟲壽命時間減少、腸道類腫瘤的組織和腹腔的轉移。我們將此模型培養至含有不同濃度的SeC（50, 100, 200, 500 μM）食物中進行治療測試，並與臨床使用的抗癌藥物Cisplatin進行療效比對，結果顯示200 μM SeC在降低幼蟲期的死亡率、延長成蟲壽命的治療效果表現最佳，並且能有效得使腸道中的類腫瘤組織縮小。我們也利用此模型與大量的變異基因果蠅品系進行遺傳分析，來了解哪些信號通路會影響SeC作用，並篩選出會對SeC治療效果造成負面影響的anti-targets，期找出更優化的治療策略，促進精準治療。
;Selenocysteine (SeC), which contains an essential micronutrient selenium (Se), has been reported to be a potential anticancer reagent. Se-containing compounds exhibit selective toxicity to multiple cancer cell lines, mainly through ROS-induced apoptosis, yet, less toxicity to normal cell. Cancer cells with higher resistance to cytostatic drugs are more sensitive to Se compounds. However, the functional mechanism of SeC is still unclear. Moreover, clinical results are inconsistent and inconclusive, partly due to dosage, different Se compounds, and genetic factors. The genetic complexity and heterogeneity of certain cancer types also make therapy discovery more challenging, for example colorectal cancer (CRC).
To gain more information, we use reported Drosophila colorectal cancer (CRC) models driven by single to triple mutants of Ras, PTEN, APC, and P53 to test the effects of SeC in a whole animal model. CRC model flies displayed observable and quantifiable phenotypes, larval lethality, shorter lifespan and gut tumor-like lesions. We treated CRC fly with different concentration of SeC (50, 100, 200, 500 μM) and compared with anticancer drug cisplatin, and examined the phenotypes aforementioned. 200 μM SeC showed greater effects in rescuing larval lethality and extending lifespan. The volumes of gut lesions were also reduced. We also performed genetic analysis by crossing with various mutant flies, aiming to identify the pathways which might influence SeC effects. This allows us to discover the “anti-targets” which reduced the efficacy of SeC in curing CRC models. In all, this study provides a platform for characterize the biological responses of Se compounds, in hope to optimize the genetic background of SeC traetment.
|
