四物湯誘導癌幹細胞對化療藥物敏感性之研究

劉嘉燿
國防醫學院
癌症之難以治療在於許多癌病經過完整化學治療後，仍舊復發，造成治療失敗及患者死亡，雖然化療藥物可以殺死絕大多數分裂中的癌細胞，但癌幹細胞對於化學治療具有抗藥性，為癌症化療之死角。癌幹細胞之所以為癌症治療之關鍵，乃因其平時處於休眠狀態 (G 0 期)，所以能逃脫化療藥物之抑制作用。如果使休眠期的癌幹細胞進入細胞週期，化學藥物治療就可以發揮其抑制癌幹細胞之作用，達到化療治癒之目的。二階段癌幹細胞療法由Trumpp實驗室研究血液幹細胞增生之機轉所提出，其第一步驟首先誘導癌幹細胞增生，再輔以化療藥物的抑制增生作用，期望可以達到抑制癌幹細胞之效果。
中醫常使用「四物湯」來緩解婦科疾病，四物是由當歸、芍藥、川芎、熟地四種藥物所組成，常用來緩解經期中的不適。本實驗室初步研究顯示，四物湯可以抑制致癌蛋白HER2 (human epidermal growth factor receptor 2) 以及發炎蛋白COX-2 (cyclooxygenase-2，環氧化酶) 的表現。此外，我們也首先發現給予四物湯接著再投予低劑量化療藥物cisplatin，可以有效抑制5-Fu抗藥性之類癌幹細胞增生。體外初步研究亦顯示，本實驗室所分離之卵巢癌幹細胞確實對抗癌藥Taxol具抗藥性。因此，四物湯輔以化療藥物作用於癌幹細胞二階段療法，在卵巢癌幹細胞是否可行，乃本計畫擬探討。
本研究擬探討四物湯與化療藥物二階段療法之適用性，由於四物湯本實驗室已在臨床證實無副作用，因此，此結果將來更有可能直接運用於臨床造福更多病患，其研究之目的包含: (1) 分離卵巢癌幹細胞，並證實此群細胞具癌幹細胞特性。(2) 四物湯是否影響癌幹細胞之細胞週期。(3) 體外與活體實驗評估四物湯與化療藥物二階段癌幹細胞治療之可行性。
關鍵字：四物湯；卵巢癌幹細胞；化療抗藥性

Study of induction of chemosensitivity in cancer stem cells by Four-Agents-Decoction

Jah-Yao Liu
National Defense Medical center
The difficulty of current cancer therapy is that cancer frequently relapses after a complete chemotherapy and causes patients’ death. Although the current chemotherapy kills most of dividing cancer cells, cancer stem cells (CSCs) are resistant to it. It is thought that the CSCs escape the killing of chemotherapeutic agents because the CSCs remain in G0 phase without entering the cell cycle. Trumpp et al. reported increasing proliferation of hematopoietic stem cells induced by interferon-α and proposed a two-step strategy in cancer chemotherapy. The dormant CSCs are first activated by factors and enter cell cycling (first step). This makes the CSCs become sensitive to chemotherapy (second step).
Four-Agents-Decoction (Si Wu Tang, FAD), an old traditional Chinese Herb formula, has been used for hundreds of years to modulate female’s discomfort during menstruation. We found that FAD downregulated HER2 and COX-2 protein expression in human endometrial cells. Also, in our lab preliminary data, the chemotherapy resistant (5-Fu resistant) cancer stem like cells become sensitive to chemotherapy after pretreated with FAD. And also, ovarian cancer stem like cells are more resistant to Taxol than ovarian cancer cells. 
In this study, we aim to isolate ovarian cancer stem cells, to study the stemness and cell cycle of these ovarian CSCs and to evaluate the two-step effects of FAD and chemotherapeutic agents on ovarian CSCs in vitro and in vivo.
關鍵字：Four-Agents-Decoction ; ovarian cancer stem cell ; chemoresistance