臺灣博碩士論文加值系統

口腔癌為發生於口腔部位惡性腫瘤之總稱，醫學上的治療方式以手術合併放射線或藥物治療為主。目前研究以尋找來源天然、副作用較弱之抗癌功效成分作為新藥或保健食品開發新方向。過去文獻指出生物活性胜?? (bioactive peptides) 有誘導癌細胞細胞週期停滯並促其凋亡程序啟動的功效，為找出抗癌效果優良的生物活性胜?成瓣F解其特性，本研究自實驗室建立之蛋白質樣本庫中取數種蛋白質水解物進行預實驗，透過MTT試驗篩選出對人類口腔鱗狀癌細胞株 HSC-3 生長抑制效果最佳之黃豆蛋白水解物 SB 與 ST 作為樣品，並探討其對口腔癌細胞株 (human tongue squamous cell carcinoma cell line,HSC-3) 細胞週期及細胞凋亡之影響進行後續探討，實驗結果如下所述：
1. 口腔癌細胞 HSC-3 存活率及半數生長抑制率 (IC50) 測定
MTT 試驗結果顯示 HSC-3 存活率隨 SB 與 ST 樣品濃度及處理時間增加而下降，並於處理 72 hr 條件下對此細胞生長抑制效果最佳，SB、ST之IC50分別為0.6 與0.74 mg/mL ，因此選定 0.25、0.5及1 mg/mL 作為後續細胞處理濃度。

2. 正常口腔角質細胞 (normal human oral keratinocyte, NHOK) 存活率測定
以選定之處理濃度測試樣品對正常細胞是否具生理毒性，MTT 試驗結果顯示 ST 對NHOK可能具生長促進活性，SB 則呈現部分生長抑制活性，但若與樣品對癌細胞 HSC-3 展現之顯著生長抑制效果相比傷害甚微，因此認定兩種樣品於此處理劑量下對正常細胞不至於造成細胞毒性。
3. 樣品對口腔癌細胞 HSC-3 細胞週期之影響
流式細胞儀分析結果顯示 SB 與 ST 處理下會使 HSC-3 處於 G0/G1 期之細胞數減少且於 S 期有顯著增加，進一步以西方墨點法檢視口腔癌細胞 HSC-3 細胞週期調控蛋白之變化，結果指出 SB 與 ST 可能藉由向下調節細胞週期蛋白 cyclin E、cyclin A 及 CDK2 之蛋白表現，使細胞週期停滯於 S 期，週期負調控蛋白 p21、p27 表現量並未隨樣品濃度增加而提升，顯示 ST 及 SB 可能透過其他路徑阻礙細胞週期運行。

4. 樣品對口腔癌細胞 HSC-3 細胞凋亡之影響
流式細胞儀分析結果顯示 SB 與 ST 處理下，可使口腔癌細胞 HSC-3 粒線體膜電位發生去極化，分析細胞分佈情形可觀察到凋亡細胞數 (Q2+Q4) 隨樣品處理濃度增加而遞增，接著藉由西方墨點法觀察樣品處理對HSC-3細胞凋亡相關蛋白之影響，結果顯示ST 處理可藉由向上調控促凋亡蛋白p53及凋亡蛋白?? cleaved caspase 9 表現，並向下調節凋亡抑制蛋白 Bcl2及凋亡蛋白?? caspase 9 及其下游 caspase 3 與 PARP 蛋白表現，透過內部路徑誘導 HSC-3 細胞走向凋亡。SB 處理組則沒有觀察到上述蛋白表現具任何顯著變化，因此推測SB可能誘導HSC-3細胞走向壞死而非凋亡。

5. 結論
綜合上述，證實黃豆蛋白水解物 ST 及 SB 中含有抗口腔癌之活性物質，且對正常細胞無毒性疑慮，製備過程簡單且花費便宜，具有開發為抗口腔癌藥物或保健食品之潛力。

Any malignant tumors located in oral cavity are collectively called oral cancer. Medical therapy strategies are mainly by combined treatments of surgery, radiation therapy, and chemotherapy. Nowadays, studies have been taking the guest for better materials that derived from natural resources with rare side effects as a new direction of developing anti-cancer drugs or healthy food. Previous studies have demonstrated that bioactive peptides have the inducing effects of cell cycle arrest and apoptosis, therefore, to discover bioactive peptides with superior anticancer efficacy and figure out their features, several hydrolysates were chosen from our database, which established by our laboratory, as samples for preliminary experiments. According to MTT assay, soybean protein hydrolysates show the best anti-proliferation effects on human tongue squamous cell carcinoma cell line (HSC-3), as the result of that, SB and ST were selected for the following experiments to investigate the effects of SB and ST on HSC-3 cells. Experimental results are shown as below.

1. Cell viability and IC50 (concentration causing 50% of cell death) determination of HSC-3
MTT assay show that proliferation of HSC-3 cell were inhibited by SB and ST in the time and dose manner, and 72-hr treatment group exhibited the most eddicacy. Since IC50 of SB and ST were 0.6 and 0.74 mg/mL, 0.25、0.5 and 1 mg/mL were selected to be the treatment dose in the following experiments.
2. Cell viability determination of normal human oral keratinocytes (NHOK)
To measure whether our samples lead to cytotoxicity in NHOK, MTT assay were used again and the data displayed that ST may promote proliferation activity of NHOK, while SB showed slightly inhibition. However, both SB and ST can be considered as no cytotoxicity when compared to their strong proliferation inhibiting ability in HSC-3 cell line under same condition.
3. Effects of samples on cell cycle in HSC-3 cell line
Flow cytometry analysis revealed that SB and ST induced cell cycle of HSC-3 to arrest in S phase by decreasing cell population in G0/G1 phase and showed a significant increasing in S phase. Western blotting were used to further access the changess of HSC-3 cell cycle regulating protein after treated with SB and ST. Data indicated that SB and ST can lead to cell cycle arrest in S phase by decreasing the expression of cyclin E, cycin A and CDK2, while the expression of cell cycle negative regulating protein p21 and p27 show no increase, which meant SB and ST might interfere the operation of cell cycle throuth the other pathway.
4. Effects of samples on apoptosis in HSC-3 cell line
Based on flow cytometry analysis, mitochondria membrane potential depolarization were observed after HSC-3 cell treated with SB and ST, and cell attribution show that population of apoptotic cells (Q2+Q4) increased after treated with SB and ST. Then western blotting was used to measure the effect of SB and ST on apoptosis related protein in HSC-3 cells. Data presented that ST can induce apoptosis in HSC-3 through intrinsic signaling pathway by increasing the expression of p53 and caspase 9,which were considered as apoptosis-promoting protein and the index of apoptosis, and decreasing the expression of Bcl2 and caspase 9, caspase 3 and PARP, which were considered as anti-apoptosis protein and apoptosis index. SB treated group did not show any significant changes above, therefore SB can be inferred to induce necrosis rather than apoptosis in HSC-3 cells.
5. Conclusion
To sum up, Soybean hydrolysates ST and SB are proved to contain the effective component with anti-oral cancer activity, while do not cause cytotoxicity to normal oral cells. Easy to produce and cost not much. Taking together, both SB and ST have great potential to be applied to anti-cancer drugs or dietary supplement developing.

目錄

目錄 I
圖目錄 IV
表目錄 V
中文摘要 VI
Abstract VIII
第一章 前言 1
第二章 文獻探討 3
第一節 蛋白質水解作用 3
一、 目的與未來發展 3
二、 水解方式 4
第二節 生物活性胜?? 5
一、 簡介 5
二、 抗菌胜?? (AMPs) 5
三、 抗氧化胜?? 6
四、 抗癌胜?? (ACPs) 6
第三節 口腔癌 8
一、 現況 8
二、 發生與病理特徵 11
三、 危險因子 13
四、 分類與分期 14
五、 治療 17
第四節 細胞週期 (cell cycle) 19
一、 簡介 19
二、 調控因子 22
三、 細胞週期與癌症 25
第五節 細胞凋亡 (Apoptosis) 26
一、 簡介 26
二、 特徵 26
三、 細胞凋亡與細胞壞死 27
四、 機轉與調控因子 29
第六節 實驗目的 32
第三章 材料方法 33
第一節 實驗設計 33
一、 實驗主架構 33
二、 預實驗設計 34
第二節 實驗藥品與儀器 36
一、 藥品 36
二、 儀器 39
第三節 實驗材料 40
一、 蛋白質原料 40
二、 商業蛋白?? 40
三、 細胞株 40
第四節 實驗方法 42
一、 水解液製備 42
二、 細胞培養 43
三、 樣品配製 47
四、 細胞存活率分析 (MTT assay) 48
五、 蛋白質萃取 50
六、 蛋白質定量 52
七、 西方墨點法 (western blot) 53
八、 細胞週期分析 (Cell cycle analysis) 63
九、 Annexin V/PI/Mito status 三染法觀測細胞凋亡 65
十、 統計分析 69
第四章 結果與討論 70
第一節 預實驗各種蛋白質水解物對人類口腔鱗狀癌細胞株HSC-3存活率之影響 70
第二節 預實驗使用樣品蛋白質之胺基酸組成 74
第三節 不同濃度黃豆蛋白水解物SB、ST對口腔癌細胞HSC-3存活率之影響 79
第四節 不同濃度SB與ST對人類正常口腔細胞NHOK存活率之影響 86
第五節 不同濃度SB與ST對人類口腔鱗狀癌細胞HSC-3細胞週期之影響 88
第六節 ST與SB誘導人類口腔鱗狀癌細胞HSC-3細胞凋亡及相關蛋白表現變化之影響 95
第五章 結論 101
第六章 參考文獻 102

 
圖目錄
圖2-1 102年台灣十大死因死亡率 9
圖2-2 台灣十大癌症死因死亡率-102年與92年 10
圖2-4 細胞週期示意圖 21
圖2-5 細胞週期調控蛋白 24
圖2-6 細胞凋亡與細胞壞死之細胞形態差異 28
圖2-7 細胞凋亡訊息傳遞路徑 31
圖3-1 實驗流程圖 33
圖4- 1 不同蛋白質水解物處理24小時對人類口腔癌細胞株HSC-3細胞存活率之影響 72
圖4- 2 不同蛋白質水解物處理48小時對人類口腔癌細胞株HSC-3細胞存活率之影響 73
(單位：MOLE/100 MOLE) 78
圖4- 3 預實驗不同樣品蛋白質來源之胺基酸組成分佈 78
圖4- 4 HSC-3經樣品SB及ST處理24小時後之細胞存活率 81
圖4- 5 HSC-3經樣品SB及ST處理48 小時後之細胞存活率 82
圖4- 6 HSC-3經樣品SB及ST處理72 小時後之細胞存活率 83
圖4- 7 HSC-3經樣品處理48小時之濃度-細胞生長抑制曲線圖 84
圖4- 8 HSC-3經樣品處理72小時之濃度-細胞生長抑制曲線圖 85
圖4- 9 不同濃度SB與ST對人類正常口腔細胞NHOK存活率之影響 87
圖4- 10 HSC-3細胞給予樣品SB處理對細胞週期之影響 90
圖4- 11 HSC-3細胞給予樣品ST處理對細胞週期之影響 91
圖4- 12 HSC-3細胞給予樣品SB及ST處理對細胞週期相關蛋白表現之影響 94
圖4- 13 HSC-3細胞給予不同濃度SB處理對細胞之影響 98
圖4- 14 HSC-3細胞給予不同濃度ST處理對細胞之影響 99
圖4- 15 HSC-3細胞給予不同濃度ST及SB處理對細胞凋亡相關蛋白表現之影響 100

表目錄
表2-1 口腔癌依組織學分類 15
表2-2 口腔癌病程TMN分期 16
表2-3 調控各細胞週期之週期蛋白及其激?? 22
表3-1 預實驗樣品與命名規則 34
表3-3 0.04N ISOPROPANOL/HCL配方 49
表3-4 蛋白裂解液配方 51
表3-5 SDS-PAGE 配方 57
表3-6 WESTERN BLOT BUFFER 配方 60
表3-7 PI染劑配方 64
表3-8 MITO STATUS RED染劑配方 68
 

1.曾瑜菀。(2010)。以商業蛋白?﹞蘢捔C魚血合肉加工副產品製備抗氧化活性胜?忖妞膍s。中國醫藥大學碩士論文。台中市。
2.楊俞萱。(2011)。鮪魚蒸煮液蛋白質水解物誘發人類乳癌細胞凋亡及細胞週期停滯之研究。中國醫藥大學碩士論文。台中市。
3.郭培棻。(2014)。鮪魚蒸煮液之活性胜?此鴾H類乳癌細胞侵襲轉移和生物利用性之評估。中國醫藥大學碩士論文。台中市。
4.Manninen, A. H. (2009).Protein hydrolysates in sports nutrition. Nutr Metab, 6:38.
5.Manley, C.H. and Ahmedi, S. (1995). The development of process flavors. Trends in Food Science & Technology, 6:46-51.
6.Turk, B. (2006). Targeting proteases: successes, failures and future prospects. Nature Reviews Drug Discovery, 5:785-99; doi:10.1038/nrd2092.
7.Tavano, O. L. (2013). Protein hydrolysis using proteases: an important tool for food biotechnology. J Mol Catal B: Enzy, 90:1-11.
8.Kitts, D. D.and Weiler, K. (2003). Bioactive proteins and peptides from food sources. applications of bioprocesses used in isolation and recovery. Curr Pharm Des, 9:1309-1323; doi:10.2174/1381612033454883.
9.Maqueda, D. M., Miralles, B., Recioa, I.and Ledesma, B. H. (2012). Antihypertensive peptides from food proteins: a review. Food and Function, 3:350-61; doi: 10.1039/C2FO10192K.
10.Zou, Y., Feng, W., Wang, W., Chen, Y., Zhou, Z., Li, Q., Zhao, T., Mao, G., Wu, X. and Yang, L. (2015). Protective effect of porcine cerebral hydrolysate peptides on learning and memory deficits and oxidative stress in lead-exposed mice. Biol Trace Elem Res.
11.Tanzadehpanah, H., Asoodeh, A. and Chamani, J. (2012). An antioxidant peptide derived from ostrich (struthio camelus) egg white protein hydrolysates. Food Res Int,49:105-11.
12.Jain, R. and Chawrai, S. (2005). Advancements in the anti-diabetes chemotherapeutics based on amino acids, peptides, and peptidomimetics. Mini-Rev Med Chem, 5:469-477; doi:10.2174/1389557053765583
13.Turpeinena, A.M., Kumpua, M., R?圢nbackb, M., Seppoa, L., Kautiainenc, H., Jauhiainena, T., Vapaatalod, H. and Korpelaa, R. (2009). Antihypertensive and cholesterol-lowering effects of a spread containing bioactive peptides IPP and VPP and plant sterols. Journal of Functional Foods, 1:260-5; doi:10.1016/j.jff.2009.03.001.
14.Stiuso, P., Caraglia, M., Rosa, G. D. and Giordano, A. (2013). Bioactive Peptides in Cancer: Therapeutic Use and Delivery Strategies. Journal of Amino Acid, Article ID 568953:2.
15.Yu, L., Yang, L,, An, W. and Su, X. (2014). Anticancer bioactive peptide-3 inhibits human gastric cancer growth by suppressing gastric cancer stem cells. J Cell Biochem, 115:697-711; doi: 10.1002/jcb.24711.
16.Robert, E., Hancock, W. and Daniel, S. C. (1999). Peptide Antibiotics. Antimicrob Agents Chemother., 43:1317-1323.
17. Brandenburg, L. O., Merres, J., Albrecht, L. J., Varoga, D., and Pufe, T. (2012). Antimicrobial Peptides: Multifunctional Drugs for Different Applications. Polymers, 4, 539-560; doi:10.3390/polym4010539.
18.Seo, M. D., Won, H. D., Kim, J. H., Tsogbadrakh, M. O. and Lee, B. J. (2012). Antimicrobial Peptides for Therapeutic Applications: A Review. Molecules, 17(10), 12276-12286; doi:10.3390/molecules171012276.
19.潘婕玉。(2005)。石斑魚抗菌蛋白基因選殖及生物功能之特性研究。國立台灣大學環境生物與漁業科學系碩士論文。台北市。
20.Yin, L. M., Edwards, M. A., Li, J., Yip, C. M. and Deber, C. M. (2012). Roles of hydrophobicity and charge distribution of cationic antimicrobial peptides in peptide-membrane Interactions. Journol of Biological Chemistry, 287:7738-7745; doi:10.1074/jbc.M111.303602.
21.王亦大，許祖法。(2008)。魚類抗菌胜?扣韝聹ˇi殖之應用潛力。農業生產技術季刊，15:34-40。
22.Cameron, E. and Pauling, L. (1976). Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A, 73(10):3685-3689.
23.Valko, M., Izakovic, M., Mazur, M., Rhodes , C. J. and Telser, J. (2004). Role of oxygen radicals in DNA damage and cancer incidence. Molecular and Cellular Biochemistry, 266: 37–56.
24.Mader, J. S. and Hoskin, D. W. (2006). Cationic antimicrobial peptides as novel cytotoxic agents for cancer treatment. Expert Opin. Invest. Drugs, 15:933-46; doi:10.1517/13543784.15.8.933.
25Torchilin, V. (2009). Intracellular delivery of protein and peptide therapeutics. Drug Discov Today Technol, 5(2-3): e95–103; doi:10.1016/j.ddtec.2009.01.002
26.van Zoggel, H., Carpentier, G., Dos Santos, C., Hamma-Kourbali, Y., Courty, J. and Amiche, M. (2012) Antitumor and angiostatic activities of the antimicrobial peptide dermaseptin B2. PLoS ONE, 7(9):e44351. doi:10.1371/journal.pone.0044351.
27.Moore, A. J., Devine, D. A., and Bibby, M. C. (1994). Preliminary experimental anticancer activity of cecropins. Pept. Res, 7(5):265–269.
28.Mader, J. S., Salsman, J., Conrad, D. M., and Hoskin, D. W. (2006). Bovine lactoferricin selectively induces apoptosis in human leukemia and carcinoma cell lines. Mol. Cancer Ther, 4:612–624. doi: 10.1158/1535-7163.MCT-04-0077.
29.Hoskin, D. W., and Ramamoorthy, A. (2008). Studies on anticancer activities of antimicrobial peptides. Biochim. Biophys. Acta, 1778:357–375; doi: 10.1016/j.bbamem.2007.11.008.
30.Berge, G., Eliassen, L. T., Camilio, K. A., Bartnes, K., Sveinbjornsson, B., and Rekdal, O. (2010). Therapeutic vaccination against a murine lymphoma by intratumoral injection of a cationic anticancer peptide. Cancer Immunol. Immunother, 59:1285–1294; doi: 10.1007/s00262-010-0857-6.
31.Schweizer, F. (2009). Cationic amphiphilic peptides with cancer-selective toxicity. Eur J Pharmacol, 625(1-3):190-4; doi: 10.1016/j.ejphar.2009.08.043.
32.Tyagi, A., Kapoor, P., Kumar, R., Chaudhary, K., Gautam, A. and Raghava, G. P. S. (2013). In silico models for designing and discovering novel anticancer peptides. Sci Rep, 3:1-8; doi: 10.1038/srep02984.
33.衛生福利部。(2013)。102年國人十大死因統計分析。
34.Vogelstein, B and Kinzler, K. W. (1993). The multistep nature of cancer. Trends Genet, 9(4):138-41.
35.Weiner, T. and Cance, W. G. (1994). Molecular mechanisms involved in tumorigenesis and their surgical implications. Am J Surg, 167(4):428-434.
36.Jurel, S. K., Gupta, D. S., Singh, R. D., Singh, M. and Srivastava, S. (2014). Genes and oral cancer. Indian J Hum Genet, 20(1): 4–9; doi: 10.4103/0971-6866.132745.
37.國家衛生研究院。(2011)。口腔癌臨床診療指引。
38.Winslow, T. (2012). Anatomy of the Oral Cavity. National Cancer Institute, Available:http://www.teresewinslow.com/portshow.asp?portfolioid=%7B4B56C61F-9C24-47C6-9F4D-9444E1D75BA2%7D.
39.Ko, Y. C., Huang, Y. L., Lee, C. H., Chen, M. J., Litt, L.M. and Tsai, C. C. (1995) Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. J Oral Pathol Med, 24: 450-453.
40.Tsai, S. T., Wong, T. Y., Ou, Y., Fang, S. Y., Chen, K. C., Hsiao, J. R., Huang, C. C., Wu, J. L., Yen, C. J., Hsueh, W. T., Wu, Y. H., Chang, J. Y., Chang, K. Y., Wu, S. Y., Liao, H. C., Lin, C. L., Wang, Y. H., Weng, Y. L., Yang, H. C. and Chang, J. S. (2014). The interplay between alcohol consumption, oral hygiene, ALDH2 and ADH1B in the risk of head and neck cancer. Int. J. Cancer, 165:2424-2436.
41.Westra, W. H. (2009). The changing face of head and neck cancer in the 21st century: the impact of HPV on the epidemiology and pathology of oral cancer. Head Neck Pathol, 3:100; doi: 10.1007/s12105-009-0100-y.
42.Edge, B. S. and Compton, C. C. (2010). The American joint committee on cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol, 17:1471-1474.
43.America Ctco, Types of oral cancer. Available: http://www.cancercenter.com/oral-cancer/types/.
44.Smith, M. L. and Fornace, A. J. (1996). Mammalian DNA damage-inducible genes associated with growth arrest and apoptosis. Mutat Res, 340:109-124.
45.Clinical Tools, http://scientopia.org/img-archive/scicurious/img_862.png
46.Donovan, J. and Slingerland, J. (2000). Transforming growth factor-beta and breast cancer: cell cycle arrest by transforming growth factor-β and its disruption in cancer. Breast Cancer Res, 2:114-124; doi:10.1186/bcr43.
47.Hollstein, M., Sidransky, D., Vogelstein, B. and Harris, C.C. (1991). p53 mutations in human cancers. Science, 5;253(5015):49-53.
48.Sidransky, D., Boyle, J. and Koch, W. (1993). Molecular screening. Prospects for a new approach. Arch Otolaryngol Head Neck Surg, 119(11):1187-90.
49.Saraste, A. and Pulkki, K. (2000). Morphologic and biochemical hallmarks of apoptosis. Cardiovasc Res Cent Bull, 45:528-537.
50.Fadok, V.A., Bratton, D.L., Rose, D.M., Pearson, A., Ezekewitz, R. A. and Henson, P. M. (2000). A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature, 405:85-90.
51.Cruchten, S. V. and Broeck, W. V. (2002). Morphological and biochemical aspects of apoptosis, oncosis and necrosis. Anat Histol Embryol, 31:214-223; doi:10.1046/j.439-0264.2002.00398.x.
52.Bortner, C. D and Cidlowski, J. A. (2002). Cellular mechanism for the repression of apoptosis. Annu Rev Pharmacol Toxicol, 42:259-281.
53.cell signaling technology, http://www.kushima.org/is/wp-content/uploads/2014/12/Apoptosis
54.Huang, Y. B., Wang, X. F., Wang, H. Y., Liu, Y. and Chen, Y. (2011). Studies on mechanism of action of anticancer peptides by modulation of hydrophobicity within a defined structural framework. Mol Cancer Ther, 10(3):416-26; doi:10.1158/1535-7163.MCT-10-0811.
55.Monera, O. D., Sereda, T. J., Zhou, N. E., Kay, C. M., and Hodges, R. S. (1995). Relationship of side-chain hydrophobicity and α-helical propensity on the stability of single-stranded amphipathic α-helix. J. Pep. Res, 1:312–329.
56.Sigma, Amino Acid Reference Chart. http://www.sigmaaldrich.com/life-science/metabolomics/learning-center/amino-acid-reference-chart.html
57.Eastoe, J. E. (1955). The amino acid composition of mammalian collagen and gelatin. Biochem J, 61:589-600.
58.陳孟君。(2013)。魚皮明膠水解物抑制 Dipeptidyl Peptidase IV 之活性及抗糖尿病功效評估。中國醫藥大學碩士論文。
59.FAQ, (1970). http://www.regional.org.au/au/roc/1988/roc198823.html.
60.Chiang, W. D., Shih, C. J. and Chu, Y. H. (1999). Functional properties of soy protein hydrolysate produced from a continuous membrane reactor system. Food Chem, 65:185-194.
61.TATUA, http://www.farbest.com/pdf/Tatua-100-Sodium-Caseinate.pdf
62.Lee, Y. K., Kim, S. Y., Kim, K. H., Chun, B. H., Lee, K. H., Oh, D. J. and Chung, N. (2008). Use of soybean protein hydrolysates for promoting proliferation of human keratinocytes in serum-free medium. Biotechnol Lett, 30(11):1931-1936; doi: 10.1007/s10529-008-9796-0.
63.Lee, Y. S., Choi, K. M., Kim, W., Jeon, Y. S., Lee, Y. M., Hong, J. T., Yun, Y. P. and Yoo, H. S. (2013). Hinokitiol inhibits cell growth through induction of s-phase arrest and apoptosis in human colon cancer cells and suppresses tumor growth in a mouse xenograft experiment. J Nat Prod, 76:2195-2202; doi:10.1021/np4005135.
64.Chen, P. Y., Lin, K. C., Lin, J. P., Tang, N. Y., Yang, J. S., Lu, K. W. and Chung, J. G. (2012). Phenethyl Isothiocyanate (PEITC) inhibits the growth of human oral squamous carcinoma HSC-3 cells through G 0 / G 1 phase arrest and mitochondria-mediated apoptotic cell death. Evid Based Complement Alternat Med, 2012:718320; doi:0.1155/2012/718320.
65.Vakkila, J. and Lotze. M. T. (2004). Inflammation and necrosis promote tumour growth. Nature Reviews Immunology, 4:641-648.
66.He, D., Li, H., Yusuf, N., Elmets, C. A., Athar, M., Katiyar, S. K. and Xu, H. (2012). IL-17 mediated inflammation promotes tumor growth and progression in the Skin. PLOS One, 7:e32126; doi:10.1371/journal.pone.0032126.
67.Zhu, Z., Shen, Z. and Xu, C. (2012). Inflammatory pathways as promising targets to increase chemotherapy response in bladder cancer. Mediators Inflamm, 2012:Article ID 528690.
68.Yazdi, ES., Bowne, W. B., Adler, V., Sookraj, K. A., Wu, V., Shteyler, V., Patel, H., Oxbury, W. and Rauf, P. B. (2010). Anticancer peptide PNC-27 adopts an HDM-2-binding conformation and kills cancer cells by binding to HDM-2 in their membranes. Archive of All Online Issues, 107:1819-1923; doi: 10.073/pnas.0909364107.
69.Wong, D. Y. Q., Lim, J. H. and Ang, W. H. (2015). Induction of targeted necrosis with HER2-targeted platinum(IV) anticancer prodrugs. Chem Sci, 2015:3051-3056; doi:10.1039/C5SC00015G.