傳統方劑對人類肝癌細胞之體內及體外抑制增生、腫瘤入侵和誘發細胞程式死亡機制之探討

林俊清
高雄醫學大學
據世界衛生組織的統計，全球約有一百萬人死於與肝癌相關的病症。在台灣，從民國八十年起，每年約有五千人死於肝癌，其中在女性的致死惡性疾病中排名第二，在男性則更高居第一名。除此，根據研究報告指出，B型肝炎病毒表面抗原的帶原者罹患肝癌的機率比非帶原者高出二百二十三倍，而依據台灣官方的統計，至少三百萬人為B型肝炎的帶原者，所以肝癌乃為傷害國人健康的頭號殺手之一。目前肝癌的治療無論在化學藥物或放射治療面臨了瓶頸，肝癌對於現行使用的抗癌藥其敏感性都不高，治療效果通常也不佳，且以肝動脈灌注化學藥物治療時所引起的副作用最大。所以，尋求一個能有效且安全的治療藥或是能預防手術後再發的有效藥物乃當務之要。 本研究目標乃從生命科學發展迅速的分子生物學理論與傳統中藥方劑之作用相互配合，深入地探索其抗肝癌之活性機轉，如此不僅可增加西方醫學對中醫藥作用的接受度，並賦與中醫藥複方藥效的現代化意義。癌症目前為威脅人類健康的頭號敵人，雖然全世界各國都投入大量的資源進行研究，但目前仍有許多困難仍需克服：其中包括許多化療藥物上不能完全殲滅癌症細胞。再者，對於一些具轉移性及複發性的癌細胞會發展出高度的抗藥性，造成治療的失敗。除此，透過血管新生的作用，癌細胞會隨血行轉移至他處。而造成癌細胞的快速擴散進而造成病人的死亡。 本計劃預計以三個階段開發出三種抗肝癌的治療策略：第一階段以直接性腫瘤毒殺的方劑為主，探討該方劑對於肝癌細胞的細胞週期及細胞凋亡誘導之效，並深入探討其對細胞週期調控 (包括p53、p21、cyclins、cdks)、細胞凋亡啟動 (包括death receptor、Bcl-2 family protein、caspases)以及相關細胞存活機制 (包括MAPK, NF-κB和PI3K/AKT)的影響。第二階段則是開發有效抑制肝癌細胞入侵及轉移的方劑，並深入探討其對相關調控機制，包括MMPs、TIMPs、NF-κB等的影響。最後一階段則是以抑制腫瘤血管新生以降低腫瘤的增生及轉移的機率，評估藥物對於血管內皮細胞的增生及血管形成的影響，並深入探討其對血管新生相關因子如HIF-α、VEGF、Ras signaling等的調控。
關鍵字：肝癌；傳統方劑；細胞凋亡；腫瘤轉移；入侵；血管新生

The mechanism of the anti-proliferative, anti-invasive and apoptotic effects of Traditional Chinese Medicinal Prescription (TCMP) in human liver cancer cells in vitro and in vivo.

Chun-Ching Lin
Kaohsiung Medical University
The incidence of cancer is increasing worldwide and it is the single most common cause of deaths in both developed and developing countries. Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, and is also one of the four most prevalent malignant diseases of adults in China, Taiwan, Korea, and sub-Africa. Several etiologic factors have been classified as high-risk factor in association with HCC, including exposure to aflatoxin B1, and infection with hepatitis B virus and hepatitis C virus. Our laboratory focuses on the integration of Traditional Chinese Medicinal Prescription (TCMP) with molecular biology to further study the active mechanism their anti-liver cancer activity. This allows a better appreciation of CTM in the modern era and also a better understanding of its underlying potential for therapy, thus increasing its acceptance in Western medicine. This research project was divided into three portions. First, we plan to assay the antiproliferative effects of these TCMP in human liver cancer cell lines, Hep G2, PLC/PRF/5 and Hep 3B, and determine the arrest of cell cycle and induction of apoptosis in these cancer cell lines. We also assess several target molecules such as p53, p21, Fas ligand, Fas receptor, Bcl-2, Bax, MAPK which are strongly associated with apoptotic pathway and are believed having something to do with the chemosensitivity？H？Hs efficacies upon anticancer drug.
關鍵字：liver cancer；TCMP；p53