癌症的化學預防就是利用萃取天然物或人工合成的化合物去阻斷、回復或預防癌症的發展。近年來，許多流行病學及動物研究已發現，存在於飲食、藥草及植物中的微量化學物質具有相當多樣的藥理特性，有益於預防多種癌症的發生。硫辛酸（α-lipoic acid, LA）是細胞可自行少量產生的雙硫化合物，主要的作用為粒線體內pyruvate dehydrogenase的輔酶，為生物膜維持正常功能的組成要素，且是一種強力的抗氧化劑及自由基清除者。而LA的還原態二氫硫辛酸（dihydrolipoic acid, DHLA）在研究中更被發現較LA擁有更好的抗氧化能力。已知許多疾病成因皆與氧化性壓力的產生有關，如：老化、癌症、發炎等。發炎反應易導致免疫相關細胞的趨化作用，進而造成ROS的產生，導致氧化性傷害。而在多步驟的致癌過程中，氧化性壓力亦已被證實在各階段均扮演很重要的角色。雖然許多研究證實LA有助於許多氧化性壓力相關疾病的治療，但是對於LA是否具有癌症預防潛能的研究，無論在體內及體外實驗仍缺乏。
本研究試圖以體外實驗將小鼠巨噬細胞RAW264.7處理內毒素（lipopolysaccharide, LPS），誘發產生一氧化氮（nitric oxide, NO）和前列腺素E2（prostaglandin E2, PGE2），並以西方墨點法測定誘發型一氧化氮合成酶（inducible NO synthase, iNOS）及環氧酶(cyclooxygenase type-2, COX-2)的蛋白表現，評估個別加入LA及DHLA的抗發炎能力。體內實驗以ICR小鼠皮膚處理TPA模式，產生發炎反應及氧化性壓力（priming和/或activation）與誘發腫瘤形成，藉由評估水腫、上皮增厚及小鼠腫瘤發生率，驗證LA/DHLA抗發炎、抗氧化及抑制腫瘤促進作用的能力。並利用LLC-bearing mice實驗模式評估LA/DHLA抑制腫瘤生長及對抗肺轉移的能力。
結果顯示，LA及DHLA皆能有效抑制由LPS誘發RAW 264.7產生的NO及PGE2，西方墨點法則觀察到iNOS蛋白表現抑制，但COX-2蛋白表現卻明顯促進的情形。體內實驗則發現DHLA可對抗ICR小鼠重複處理TPA造成的發炎反應（白血球滲透（priming）及白血球的氧化性傷害（activation）），而達到抑制水腫及上皮增生的效果，LA則無抑制能力。皮膚前處理DHLA抑制ICR小鼠兩階段DMBA/TPA誘發產生腫瘤的實驗，顯示DHLA抗腫瘤促進作用的能力較Resveratrol好。以LLC-bearing mice實驗模式連續腹腔注射給藥33天顯示LA並無抑制腫瘤生長及對抗肺轉移的能力。
綜合上述結果，LA/DHLA在抗發炎、抗氧化及抗腫瘤促進作用方面有一定程度的效果，然而在抗腫瘤生長及抗轉移的能力方面並無顯著效果，因此，LA/DHLA在癌症化學預防上可能扮演的角色仍須更進一步的研究加以釐清。

Cancer chemoprevention is defined as interruption, recovery or prevention of cancer developing by natural occurring or synthetic compounds. In recent years, many epidemiological and animal studies have suggested that microchemicals present in the diet, herbs and plants with pharmacological properties are useful agents for the prevention of a wide variety of human cancers. Alpha-lipoic acid (LA) is a disulfide compound that is produced in small quantities in cells, and functions naturally as a co-enzyme in the pyruvate dehydrogenase. It is also a physiological constituent of biological membranes, an efficient antioxidant and a scavenger of free radicals. Dihydrolipoic acid (DHLA), formed by reduction of LA, has been shown to possess more antioxidant properties than does LA. Oxidative stress has been revealed to be related to several diseases such as aging, cancer and inflammation. Among these, reactive oxygen species（ROS）play a pivotal role in the process of inflammation and multiple step carcinogenesis. Several studies also showed that treatment of LA is beneficial for many diseases caused by oxidative damage. However, there are scanty data with respect to anti-tumorigenesis activity of LA.
In the present works, we conducted the in vitro anti-inflammatory study to assess the effects of LA/DHLA on nitric oxide (NO) and prostaglandin E2 (PGE2) generation in RAW264.7 macrophages stimulated by lipopolysaccharide (LPS). Expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase type-2 (COX-2) proteins were assayed by western blotting. The in vivo short-term anti-inflammatory, anti-oxidative and long-term anti-tumor promoting activities of LA/DHLA were evaluated by topical TPA application to ICR mouse skin with measurement of edema formation, epidermal thickness, and incidence of tumor-bearing mice. In addition, the potency of anti-tumor growth and anti-metastasis of LA were also analyzed by using Lewis lung carcinoma-bearing mice experimental model.
We have demonstrated that LA and DHLA strongly suppressed the NO and PGE2 release in LPS-treated RAW264.7 cells. Western blot showedt down-regulation of iNOS, but up-regulation of COX-2 expression after treated with LA and DHLA in LPS-treated cells. In in vivo studies, we found that DHLA but not LA significantly inhibited skin inflammation induced by double TPA application by decreasing the edema and epidermal hyperplasia formation. Inhibitory effects of tumor promotion showed that DHLA possess higher anti-tumor promotic ability than the resveratrol in DMBA-initiated ICR mice. However, LA shows no inhibition effects of tumor growth and lung metastasis in LLC-bearing mice experimental model.
In summary, the data presented here indicate that LA/DHLA possess significant effects in anti-inflammation, anti-oxidation and anti-tumor promotion. Whereas, no effects were found in anti-tumor growth and anti-metastasis. Thus, more studies are needed to further elucidate the role of LA/DHLA in cancer chemoprevention.

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