腎細胞癌是台灣十大死因之一。早期的腎癌可以藉由手術切除達到治療的目的。但早期不易得到確定診斷，所以大多在癌症發生轉移時才被診斷出來。而腎癌發展到晚期大多會產生轉移性腎細胞癌，治癒力很低。現今在治療晚期或轉移性腎細胞癌的標靶藥物，大多針對Vascular endothelial growth factor receptor (VEGFR) 或 receptor protein tyrosine kinases(RTKs) 做設計。目前臨床用藥sunitinib，是屬於tyrosine kinase inhibitors (TKI) 可以抑制癌細胞生長以及抑制癌細胞轉移，常用來治療renal cell carcinoma (RCC) 和 gastrointestinal stromal tumor (GIST) 。但sunitinib是透過何分子來抑制細胞轉移，其機制並不清楚。過去探討其影響細胞轉移的機轉，主要是抑制 PI3K/AKT/mTOR 這條路徑。但仍有更多的路徑與分子會參與細胞的轉移與侵入。而本論文進一步發現，在前處理sunitinib過後的確會降低 MMP-2 和 MMP-9 分解蛋白的活性，並能有效抑制細胞轉移和侵入能力。另外本篇論文使用的中草藥 luteolin，過去被探討會透過 AKT pathway 來抑制肺癌細胞轉移。本實驗結果也顯示在腎癌中，Luteolin與sunitinib都能抑制MMP-2 和 MMP-9 的分解活性。使細胞間質不易被破壞，讓癌細胞無法轉移。實驗也發現， MMP-2 和 MMP-9 的分解活性下降與 AKT的失活及 CEP55 表現量下降是正相關，但是目前之研究數據無法證明兩者之間的直接相關性。必須進一步釐清影響細胞轉移的分子機轉。以及是否能透過與 luteolin合併使用，降低 sunitinib 副作用的產生，直接應用於臨床治療腎癌病人，是值得繼續探討的問題。
Renal cell carcinoma (RCC) is a heterogeneous disease with dismal outcome. Sunitinib is an inhibitor of multiple tyrosine kinase receptors approved for the oral treatment of metastatic RCC. Luteolin, a natural flavonoid wildly existing in plants including fruits, vegetables, and medicinal herbs, has potent anti-cancer property. Previous studies show that luteolin sensitizes cancer cells to therapeutic-induced cytotoxicity through suppressing cell survival pathways. Growing evidence indicate that luteolin can be an anticancer agent for various cancers. However, the precise mechanism of sunitinib and luteolin action against RCC remains largely unclear and requires further investigation. For this purpose, this study was conducted using human RCC 786-0 cell line to examine the effects of sunitinib and luteolin on RCC invasion in in vitro cell culture system. Our results showed that sunitinib and luteolin alone inhibited cell growth of 786-0 cells with IC50 values of 4.1 and 28.7 uM after 48 h treatment. Moreover, sunitinib and luteolin could inhibit768-0 cell migration and invasion as well as MMP-2 and MMP-9 enzyme activity and gene expression. These events were accompanied by AKT inactivation and CEP55 downregulation. These findings indicate that sunitinib- and luteolin-mediated growth inhibition, invasion suppression, and MMPs downregulation might be via the inactivation of AKT-dependent pathway in RCC cells.
