異白花丹素 (Isoplumbagin) 是一個存在於散沫花和白丹花中的天然醌類分子，已有研究證實其具有抗發炎和抗菌的功能。雖然異白花丹素具有抗襲性陰道炎菌株的作用，但是其在抗癌症方面的功能仍然未知。在這個研究中，我們利用化學合成的異白花丹素對侵襲性人類口腔鱗狀癌細胞 (OC3-IV2) 的抗癌能力進行評估。我們的數據藉由使用MTT和boyden chamber試驗證明了異白花丹素對OC3-IV2細胞的增殖和侵襲具有抑制作用。在體內實驗的研究中，給予口腔異體移植模型小鼠每公斤2毫克劑量的異白花丹素 亦能有效抑制其口腔中腫瘤的生長。我們進一步確定異白花丹素是菸草醯胺腺嘌呤二核苷酸磷酸鹽-醌去氫酶1 (NQO1) 蛋白的受質，然後發現異白花丹素針對NQO1蛋白所造成OC3-IV2細胞死亡是由於抑制線粒體耗氧率，特別是藉由抑制電子傳遞鏈中復合物IV的活性，而不是增加細胞內活性氧化物的水平或去氧核醣核酸斷裂。結合這些結果，我們得出結論，異白花丹素對於口腔癌可以潛在地提供一個有效的治療。

Isoplumbagin (5-hydroxy-3-methyl-1,4-naphthoquinone) is a naturally occurring quinone from Lawsonia inermis and Plumbago europaea that has been reported to have anti-inflammatory and anti-microbial activity. While it has been shown that isoplumbagin has anti-microbial activity against invasive vaginitis strains, its function in anti-cancer activity is remain largely unknown. In this study, we assessed the anti-cancer activity of chemically-synthesized isoplumbagin in human highly invasive oral squamous cell carcinoma (OSCC) OC3-IV2 cells. Our data demonstrated the inhibitory effects of isoplumbagin on proliferation and invasion of OC3-IV2 cells by using MTT and boyden chamber assays. In the in vivo study, 2 mg/kg isoplumbagin administration also inhibited tumor growth efficiently in oral cavity xenograft models. We further identified isoplumbagin as a substrate of NAD(P)H quinone dehydrogenase 1 (NQO1) protein. Then, we found isoplumbagin causes OC3-IV2 cells died by targeting NQO1 is owing to suppressing mitochondrial oxygen consumption rates especially by inhibiting the activity of complex IV within the electron transport chain, but not increasing ROS level nor DNA fragmentation. Together these data, we conclude that isoplumbagin could potentially offer an effective oral cancer therapy.

Abstract I
摘要 II
Acknowledgements III
Table of contents 1
Introduction 5
Oral cancer 5
Novel drugs 6
Natural compounds 7
NAD(P)H dehydrogenase [quinone] 1 (NQO1) 9
Mitochondria 9
Material and Methods 12
Cell lines 12
Reagents 12
MTT assays 13
Boyden chamber assays 13
In vivo xenograft mice model 14
Molecular ducking 15
NQO1 activity assay 15
Immunoblotting 16
Reactive oxygen species assays 17
TUNEL assays 17
High-resolution respirometry 18
Statistical analysis 18
Results 20
Screening for plants extracts that have anti-cancer activity 20
Isoplumbagin suppresses cell proliferation and invasion in OC3-IV2 cells 21
Isoplumbagin inhibits tumor growth in an OSCC xenograft model 22
Identification of NAD(P)H dehydrogenase [quinone] 1 (NQO1) as a candidate target of isoplumbagin 23
Isoplumbagin is a substrate of NQO1 24
NQO1 levels vary in different types of cancer 24
Isoplumbagin does not increase ROS level nor DNA fragmentation invasive OC3-IV2 cells 26
Isoplumbagin regulates mitochondrial morphogenesis and respiration in the highly invasive OC3-IV2 cells 27
Conclusion 29
Discussion 30
Figure 32
Figure 1. The chemical structure of plumbagin and isoplumbagin. 32
Figure 2. The effect of plumbagin on migration and invasion for invasive oral squamous cell carcinoma cells (OC3-IV2). 33
Figure 3. The effect of isoplumbagin on survival of highly invasive oral squamous cell carcinoma cells (OC3-IV2). 34
Figure 4. The effect of isoplumbagin on invasion for highly invasive oral squamous cell carcinoma cells (OC3-IV2) and human cervical cancer cells (Hela). 35
Figure 5. The effect of isoplumbagin in orthotopic xenograft mice model. 36
Figure 6. identification of candidate targets of isoplumbagin. 37
Figure 7. Isoplumbagin is a substrate of NQO1. 39
Figure 8. NQO1 levels in cancer cell lines. 40
Figure 9. The effect of dicumarol on survival of OC3-IV2 cells. 41
Figure 10. The effect of isoplumbagin on intracellular oxidative stress and DNA damage of OSCC cells. 42
Figure 11. The effect of isoplumbagin on mitochondrial respiration and complex activity of OC3-IV2 cells. 44
Figure 12. Molecule docking of plumbagin and NQO1 homodimer. 46
Figure 13. The effect of plumbagin on mitochondrial respiration and complex activity of OC3-IV2 cells. 47
Table 49
Table 1. Anticancer abilities between isoplumbagin and plumbagin. 49
References 50

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