臺灣博碩士論文加值系統

口腔癌是全世界十大常見癌症之一。去甲氧基薑黃素(demethoxycurcumin，DMC)為薑黃中最具活性的薑黃類似物成分之一，已被提出具有抗發炎、抗菌及抗氧化等功效，此外DMC更被證實能有效抑制多種癌細胞的生長，然而對於DMC與口腔癌之間的相關性尚未被釐清，因此本篇主要探討DMC在口腔癌之抗癌作用。首先，在細胞存活試驗中可以發現到DMC有效抑制人類口腔癌細胞HSC-3的生長。接著，利用流式細胞儀觀察細胞週期的變化，DMC隨著濃度增加，sub-G1族群的累積也隨之上升，推測DMC能促使HSC-3細胞產生凋亡。在AnnexinV/PI雙染實驗中更進一步證實，DMC會使HSC-3走向細胞凋亡。進一步想去釐清DMC誘導HSC-3細胞凋亡的相關分子調控機制。結果顯示，DMC可經由細胞凋亡外在路徑或是粒線體內在路徑分別增加切割活化態之caspase-8及caspase-9的表現，再活化下游caspase-3，並造成Poly(ADP-ribose)polymerase-1(PARP)裂解，最終誘發細胞凋亡。此外，DMC可促使JNK1/2及p38蛋白磷酸化，並利用相關抑制劑可以證實DMC會增加p38的磷酸化以促使caspase蛋白的活化。總結上述實驗DMC會經由p38的路徑誘導細胞凋亡蛋白caspase-8、caspase-9及caspase-3的活化，進一步使下游蛋白PARP裂解，而造成細胞凋亡的發生，這也顯示出DMC能作為口腔癌的治療新策略。

Oral cancer is one of the top ten most common cancers in the world.Curcuminoids are the most active components in turmeric (Curcumalonga), and the curcuminoids Demethoxycurcumin (DMC) has beenshown to exhibit anti-inflammatory, anti-bacterial, anti-fungal, and antioxidanteffects. DMC has also been reported to suppress cell growth andto induce cell death in various cancers. However, the effects of DMC onoral cancer are still unclear. In the present study, results show that DMCsignificantly inhibited cell growth of HSC-3 human oral cancer cells.Moreover, DMC increased the sub-G1 proportion of the cell cycle analysis.Using Annexin V/PI double staining, we confirmed that DMC triggeredapoptosis in HSC-3 cells. In addition, DMC induced apoptosis throughcaspase-8, caspase-9 and caspase-3 activation and PARP cleavage in HSC-3 cells. Furthermore, treatment of HSC-3 cells with DMC increased thephosphorylation of JNK1/2 and p38 and inhibition of p38 by the specificinhibitor abolished DMC-induced cell apoptosis. In summary, these resultsindicate that DMC induces apoptosis in HSC-3 cells through a p38-mediated apoptotic pathway and could be a new strategy for treating oralcancer.

壹、 中文摘要 ...........................................4
貳、 英文摘要 ...........................................5
參、 縮寫檢索表 .........................................6
肆、 緒論 ...............................................8
一、 口腔癌 (oral cancer) ...............................8
二、 去甲氧基薑黃素 (demethoxycurcumin，DMC) ............11
三、 細胞凋亡 (apoptosis) ..............................13
四、 MAPK 調控路徑 .....................................16
伍、 研究動機 ..........................................22
陸、 實驗材料與方法 ....................................23
一、 藥品試劑 ..........................................23
二、 實驗設備 ..........................................24
三、 實驗細胞株 ........................................25
柒、 實驗方法 ..........................................26
一、 細胞培養 (cell culture) ...........................26
二、 細胞存活率測試(analysis of cell viability).........28
三、 細胞週期分析 (cell cycle analysis) ................30
四、 細胞凋亡分析 (cell apoptosis analysis) ............31
五、 西方點墨法 (Western blot) .........................33
六、 統計分析 (statistical analysis) ...................40
捌、 實驗結果 ..........................................41
一、 DMC 可抑制人類口腔癌細胞的生長 ......................41
二、 DMC 可促使人類口腔癌細胞之細胞週期sub-G1 期增加 .....41
三、 DMC 可誘導人類口腔癌細胞之細胞凋亡的發生 ............42
四、 DMC 促進caspase 蛋白的活化以達到促使人類口腔癌細胞細
胞死亡 ................................................43
五、 DMC 增加訊息傳遞路徑MAPK 蛋白JNK 以及p38 的磷酸化
表現...................................................43
六、 DMC 可經由p38 MAPK 蛋白的活化誘使人類口腔癌細胞細
胞凋亡.................................................44
玖、 討論 ..............................................46
壹拾、 參考文獻 ........................................51
壹拾壹、 圖表與圖表說明 .................................61
Figure 1. 探討DMC 對於人類口腔癌細胞株HSC-3 細胞存活之影
響.....................................................62
Figure 2. DMC 對於人類口腔癌細胞株HSC-3 細胞週期之影響 ...64
Figure 3. DMC 對於人類口腔癌細胞株HSC-3 細胞凋亡之變化 ...66
Figure 4. 探討DMC 對於人類口腔癌細胞株HSC-3 細胞凋亡之相
關蛋白表現 .............................................68
Figure 5. 探討DMC 對於人類口腔癌細胞株HSC-3 MAPK 路徑相
關蛋白的表現 ...........................................70
Figure 6. 探討MAPK 抑制劑對於DMC 誘導人類口腔癌細胞株
HSC-3 細胞凋亡之影響。 .................................72
Figure 7. DMC 誘導人類口腔癌細胞株HSC-3 細胞凋亡之調控機制
圖.....................................................73
附錄 ..................................................74
附錄一、口腔癌之TNM 分期標準 ............................75
附錄二、口腔癌之臨床分期 ................................76

Abou-Ghali, M., and J. Stiban. 2015. ''Regulation of ceramide channel formation and disassembly: Insights on the initiation of apoptosis'', Saudi J Biol Sci, 22: 760-72.
Allegra, A., V. Innao, S. Russo, D. Gerace, A. Alonci, and C. Musolino. 2017. ''Anticancer Activity of Curcumin and Its Analogues: Preclinical and Clinical Studies'', Cancer Invest, 35: 1-22.
Anand, P., S. G. Thomas, A. B. Kunnumakkara, C. Sundaram, K. B. Harikumar, B. Sung, S. T. Tharakan, K. Misra, I. K. Priyadarsini, K. N. Rajasekharan, and B. B. Aggarwal. 2008. ''Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature'', Biochem Pharmacol, 76: 1590-611.
Aoki, H., P. M. Kang, J. Hampe, K. Yoshimura, T. Noma, M. Matsuzaki, and S. Izumo. 2002. ''Direct activation of mitochondrial apoptosis machinery by c-Jun N-terminal kinase in adult cardiac myocytes'', J Biol Chem, 277: 10244-50.
Bettendorf, O., J. Piffko, and A. Bankfalvi. 2004. ''Prognostic and predictive factors in oral squamous cell cancer: important tools for planning individual therapy?'', Oral Oncol, 40: 110-9.
Billecke, C., S. Finniss, L. Tahash, C. Miller, T. Mikkelsen, N. P. Farrell, and O. Bogler. 2006. ''Polynuclear platinum anticancer drugs are more potent than cisplatin and induce cell cycle arrest in glioma'', Neuro Oncol, 8: 215-26.
Bradham, C., and D. R. McClay. 2006. ''p38 MAPK in development and cancer'', Cell Cycle, 5: 824-8. Cargnello, M., and P. P. Roux. 2011. ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases'', Microbiol Mol Biol Rev, 75: 50-83.
Chen, Z., T. B. Gibson, F. Robinson, L. Silvestro, G. Pearson, B. Xu, A. Wright, C. Vanderbilt, and M. H. Cobb. 2001. ''MAP kinases'', Chem Rev, 101: 2449-76.
Cheung, E. C., and R. S. Slack. 2004. ''Emerging role for ERK as a key regulator of neuronal apoptosis'', Sci STKE, 2004: Pe45.
Chin, K. Y. 2016. ''The spice for joint inflammation: anti-inflammatory role
of curcumin in treating osteoarthritis'', Drug Des Devel Ther, 10:
3029-42.
Choudhari, S. K., M. Chaudhary, A. R. Gadbail, A. Sharma, and S. Tekade. 2014. ''Oxidative and antioxidative mechanisms in oral cancer and precancer: a review'', Oral Oncol, 50: 10-8.
Choudhuri, T., S. Pal, T. Das, and G. Sa. 2005. ''Curcumin selectively induces apoptosis in deregulated cyclin D1-expressed cells at G2 phase of cell cycle in a p53-dependent manner'', J Biol Chem, 280: 20059-68.
Chuah, A. M., B. Jacob, Z. Jie, S. Ramesh, S. Mandal, J. K. Puthan, P. Deshpande, V. V. Vaidyanathan, R. W. Gelling, G. Patel, T. Das, and S. Shreeram. 2014. ''Enhanced bioavailability and bioefficacy of an amorphous solid dispersion of curcumin'', Food Chem, 156: 227-33.
Chuang, S. L., W. W. Su, S. L. Chen, A. M. Yen, C. P. Wang, J. C. Fann, S.Y. Chiu, Y. C. Lee, H. M. Chiu, D. C. Chang, Y. Y. Jou, C. Y. Wu, H. H. Chen, M. K. Chen, and S. T. Chiou. 2017. ''Population-based screening program for reducing oral cancer mortality in 2,334,299 Taiwanese cigarette smokers and/or betel quid chewers'', Cancer, 123: 1597-609.
Cuffari, L., J. T. Tesseroli de Siqueira, K. Nemr, and A. Rapaport. 2006. ''Pain complaint as the first symptom of oral cancer: a descriptive study'', Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 102: 56-61.
Day, T. A., B. K. Davis, M. B. Gillespie, J. K. Joe, M. Kibbey, B. Martin- Harris, B. Neville, M. S. Richardson, S. Rosenzweig, A. K. Sharma, M. M. Smith, S. Stewart, and R. K. Stuart. 2003. ''Oral cancer treatment'', Curr Treat Options Oncol, 4: 27-41.
De Zutter, G. S., and R. J. Davis. 2001. ''Pro-apoptotic gene expression mediated by the p38 mitogen-activated protein kinase signal transduction pathway'', Proc Natl Acad Sci U S A, 98: 6168-73.
Derradji, H., and S. Baatout. 2003. ''Apoptosis: a mechanism of cell suicide'',
In Vivo, 17: 185-92.
Devi, Y. S., M. DeVine, J. DeKuiper, S. Ferguson, and A. T. Fazleabas. 2015. ''Inhibition of IL-6 signaling pathway by curcumin in uterine decidual cells'', PLoS One, 10: e0125627.
Dhanasekaran, D. N., and E. P. Reddy. 2008. ''JNK signaling in apoptosis'', Oncogene, 27: 6245-51.
Erdem, N. F., E. R. Carlson, and D. A. Gerard. 2008. ''Characterization of gene expression profiles of 3 different human oral squamous cell carcinoma cell lines with different invasion and metastatic capacities'', J Oral Maxillofac Surg, 66: 918-27.
Erdem, N. F., E. R. Carlson, D. A. Gerard, and A. T. Ichiki. 2007. ''Characterization of 3 oral squamous cell carcinoma cell lines with different invasion and/or metastatic potentials'', J Oral Maxillofac Surg, 65: 1725-33.
Fan, M., and T. C. Chambers. 2001. ''Role of mitogen-activated protein kinases in the response of tumor cells to chemotherapy'', Drug Resist Updat, 4: 253-67.
Fidler, I. J. 2003. ''The pathogenesis of cancer metastasis: the ''seed and soil'' hypothesis revisited'', Nat Rev Cancer, 3: 453-8. Gera, M., N. Sharma, M. Ghosh, D. L. Huynh, S. J. Lee, T. Min, T. Kwon, and D. K. Jeong. 2017. ''Nanoformulations of curcumin: an emerging paradigm for improved remedial application'', Oncotarget, 8: 66680-98.
Goel, A., A. B. Kunnumakkara, and B. B. Aggarwal. 2008. ''Curcumin as "Curecumin": from kitchen to clinic'', Biochem Pharmacol, 75: 787- 809.
Guneri, P., and J. B. Epstein. 2014. ''Late stage diagnosis of oral cancer: components and possible solutions'', Oral Oncol, 50: 1131-6. Han, G., R. Bi, Q. Le, L. L. Zhao, Y. Dong, and Q. H. Lin. 2008. ''[Study on effect of demethoxycurcumin in Curcuma long on stability of curcumin]'', Zhong Yao Cai, 31: 592-4.
Han, J., J. D. Lee, L. Bibbs, and R. J. Ulevitch. 1994. ''A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells'', Science, 265: 808-11.
Hanahan, D., and R. A. Weinberg. 2000. ''The hallmarks of cancer'', Cell, 100: 57-70.
Hassan, H. E., S. Carlson, I. Abdallah, T. Buttolph, K. C. Glass, and T. E. Fandy. 2015. ''Curcumin and dimethoxycurcumin induced epigenetic changes in leukemia cells'', Pharm Res, 32: 863-75.
Hatamipour, M., M. Ramezani, S. A. S. Tabassi, T. P. Johnston, M. Ramezani, and A. Sahebkar. 2018. ''Demethoxycurcumin: A naturally occurring curcumin analogue with antitumor properties'', J Cell Physiol, 233: 9247-60.
Hotchkiss, R. S., A. Strasser, J. E. McDunn, and P. E. Swanson. 2009. ''Cell death'', N Engl J Med, 361: 1570-83.
Huang, S. H., and B. O''Sullivan. 2013. ''Oral cancer: Current role of radiotherapy and chemotherapy'', Med Oral Patol Oral Cir Bucal, 18: e233-40.
Huang, T. Y., C. W. Hsu, W. C. Chang, M. Y. Wang, J. F. Wu, and Y. C. Hsu. 2012. ''Demethoxycurcumin Retards Cell Growth and Induces Apoptosis in Human Brain Malignant Glioma GBM 8401 Cells'', Evid Based Complement Alternat Med, 2012: 396573.
Ichim, G., and S. W. Tait. 2016. ''A fate worse than death: apoptosis as an oncogenic process'', Nat Rev Cancer, 16: 539-48.
Jankun, J., M. Wyganowska-Swiatkowska, K. Dettlaff, A. Jelinska, A. Surdacka, D. Watrobska-Swietlikowska, and E. Skrzypczak-Jankun. 2016. ''Determining whether curcumin degradation/condensation is actually bioactivation (Review)'', Int J Mol Med, 37: 1151-8.
Jo, S. K., W. Y. Cho, S. A. Sung, H. K. Kim, and N. H. Won. 2005. ''MEK inhibitor, U0126, attenuates cisplatin-induced renal injury by decreasing inflammation and apoptosis'', Kidney Int, 67: 458-66.
Kalu, N. N., T. Mazumdar, S. Peng, L. Shen, V. Sambandam, X. Rao, Y. Xi, L. Li, Y. Qi, F. O. Gleber-Netto, A. Patel, J. Wang, M. J. Frederick, J. N. Myers, C. R. Pickering, and F. M. Johnson. 2017. ''Genomic characterization of human papillomavirus-positive and negative human squamous cell cancer cell lines'', Oncotarget, 8: 86369-83.
Katsidoni, V., P. Alexiou, M. Fotiadou, M. Pelecanou, M. Sagnou, and G. Panagis. 2014. ''Curcumin, demethoxycurcumin and bisdemethoxycurcumin differentially inhibit morphine''s rewarding effect in rats'', Psychopharmacology (Berl), 231: 4467-78.
Kertia, N., A. H. Asdie, W. Rochmah, and Marsetyawan. 2012. ''Ability of curcuminoid compared to diclofenac sodium in reducing the secretion of cycloxygenase-2 enzyme by synovial fluid''s monocytes of patients with osteoarthritis'', Acta Med Indones, 44: 105-13.
Kim, J. S., D. Oh, M. J. Yim, J. J. Park, K. R. Kang, I. A. Cho, S. M. Moon, J. S. Oh, J. S. You, C. S. Kim, D. K. Kim, S. Y. Lee, G. J. Lee, H. J. Im, and S. G. Kim. 2015. ''Berberine induces FasL-related apoptosis through p38 activation in KB human oral cancer cells'', Oncol Rep, 33: 1775-82.
Kim, Y. K., H. J. Kim, C. H. Kwon, J. H. Kim, J. S. Woo, J. S. Jung, and J. M. Kim. 2005. ''Role of ERK activation in cisplatin-induced apoptosis in OK renal epithelial cells'', J Appl Toxicol, 25: 374-82.
Ko, Y. C., S. C. Hsu, H. C. Liu, Y. T. Hsiao, T. C. Hsia, S. T. Yang, W. H. Hsu, and J. G. Chung. 2015. ''Demethoxycurcumin alters gene expression associated with DNA damage, cell cycle and apoptosis in human lung cancer NCI-H460 cells in vitro'', In Vivo, 29: 83-94.
Ko, Y. C., J. C. Lien, H. C. Liu, S. C. Hsu, B. C. Ji, M. D. Yang, W. H. Hsu, and J. G. Chung. 2015. ''Demethoxycurcumin induces the apoptosis of human lung cancer NCI-H460 cells through the mitochondrial dependent pathway'', Oncol Rep, 33: 2429-37.
Kowalski, L. P., and A. L. Carvalho. 2000. ''Natural history of untreated head and neck cancer'', Eur J Cancer, 36: 1032-7.
Kumar, M., R. Nanavati, T. G. Modi, and C. Dobariya. 2016. ''Oral cancer: Etiology and risk factors: A review'', J Cancer Res Ther, 12: 458-63.
Kumar, P., K. Sulakhiya, C. C. Barua, and N. Mundhe. 2017. ''TNF-alpha, IL-6 and IL-10 expressions, responsible for disparity in action of curcumin against cisplatin-induced nephrotoxicity in rats'', Mol Cell Biochem, 431: 113-22.
Kunwar, A., S. Jayakumar, A. K. Srivastava, and K. I. Priyadarsini. 2012. ''Dimethoxycurcumin-induced cell death in human breast carcinoma MCF7 cells: evidence for pro-oxidant activity, mitochondrial dysfunction, and apoptosis'', Arch Toxicol, 86: 603-14.
Kurien, B. T., A. Singh, H. Matsumoto, and R. H. Scofield. 2007. ''Improving the solubility and pharmacological efficacy of curcumin by heat treatment'', Assay Drug Dev Technol, 5: 567-76.
Kyriakis, J. M., and J. Avruch. 2001. ''Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation'', Physiol Rev, 81: 807-69.
Lee, J. C., J. T. Laydon, P. C. McDonnell, T. F. Gallagher, S. Kumar, D. Green, D. McNulty, M. J. Blumenthal, J. R. Heys, S. W. Landvatter, J. E. Strickler, M. M. McLaughlin, I. R. Siemens, S. M. Fisher, G. P. Livi, J. R. White, J. L. Adams, and P. R. Young. 1994. ''A protein kinase involved in the regulation of inflammatory cytokine biosynthesis'', Nature, 372: 739-46.
Lee, J., V. Taneja, and R. Vassallo. 2012. ''Cigarette smoking and inflammation: cellular and molecular mechanisms'', J Dent Res, 91: 142-9.
Lee, J. W., H. M. Hong, D. D. Kwon, H. O. Pae, and H. J. Jeong. 2010. ''Dimethoxycurcumin, a structural analogue of curcumin, induces apoptosis in human renal carcinoma caki cells through the production of reactive oxygen species, the release of cytochrome C, and the activation of caspase-3'', Korean J Urol, 51: 870-8.
Lei, K., A. Nimnual, W. X. Zong, N. J. Kennedy, R. A. Flavell, C. B. Thompson, D. Bar-Sagi, and R. J. Davis. 2002. ''The Bax subfamily of Bcl2-related proteins is essential for apoptotic signal transduction by c-Jun NH(2)-terminal kinase'', Mol Cell Biol, 22: 4929-42.
Lichota, A., and K. Gwozdzinski. 2018. ''Anticancer Activity of Natural Compounds from Plant and Marine Environment'', Int J Mol Sci, 19.
Lin, C. J., J. R. Grandis, T. E. Carey, S. M. Gollin, T. L. Whiteside, W. M. Koch, R. L. Ferris, and S. Y. Lai. 2007. ''Head and neck squamous cell carcinoma cell lines: established models and rationale for selection'', Head Neck, 29: 163-88.
Lu, Z., and S. Xu. 2006. ''ERK1/2 MAP kinases in cell survival and apoptosis'', IUBMB Life, 58: 621-31.
Mackenzie, G. G., N. Queisser, M. L. Wolfson, C. G. Fraga, A. M. Adamo, and P. I. Oteiza. 2008. ''Curcumin induces cell-arrest and apoptosis in association with the inhibition of constitutively active NF-kappaB and STAT3 pathways in Hodgkin''s lymphoma cells'', Int J Cancer, 123: 56-65.
Madesh, M., B. Antonsson, S. M. Srinivasula, E. S. Alnemri, and G. Hajnoczky. 2002. ''Rapid kinetics of tBid-induced cytochrome c and Smac/DIABLO release and mitochondrial depolarization'', J Biol Chem, 277: 5651-9.
Milian, A., J. V. Bagan, and F. Vera. 1993. ''Squamous cell carcinoma of the oral cavity: a follow up study of 85 cases and analysis of prognostic variables'', Bull Group Int Rech Sci Stomatol Odontol, 36: 29-35.
Mohammadi, S., P. Kayedpoor, L. Karimzadeh-Bardei, and M. Nabiuni. 2017. ''The Effect of Curcumin on TNF-alpha, IL-6 and CRP Expression in a Model of Polycystic Ovary Syndrome as an Inflammation State'', J Reprod Infertil, 18: 352-60.
Munigunti, R., S. Gathiaka, O. Acevedo, R. Sahu, B. Tekwani, and A. I. Calderon. 2014. ''Determination of antiplasmodial activity and binding affinity of curcumin and demethoxycurcumin towards PfTrxR'', Nat Prod Res, 28: 359-64.
Olson, J. M., and A. R. Hallahan. 2004. ''p38 MAP kinase: a convergence point in cancer therapy'', Trends Mol Med, 10: 125-9.
Pan, J., L. Zhang, S. Xu, X. Cheng, H. Yu, J. Bao, and R. Lu. 2018. ''Induction of Apoptosis in Human Papillary-Thyroid-Carcinoma BCPAP Cells by Diallyl Trisulfide through Activation of the MAPK Signaling Pathway'', J Agric Food Chem, 66: 5871-78.
Panahi, Y., N. Khalili, E. Sahebi, S. Namazi, M. S. Karimian, M. Majeed, and A. Sahebkar. 2017. ''Antioxidant effects of curcuminoids in patients with type 2 diabetes mellitus: a randomized controlled trial'', Inflammopharmacology, 25: 25-31.
Park, M. T., J. A. Choi, M. J. Kim, H. D. Um, S. Bae, C. M. Kang, C. K. Cho, S. Kang, H. Y. Chung, Y. S. Lee, and S. J. Lee. 2003. ''Suppression of extracellular signal-related kinase and activation of p38 MAPK are two critical events leading to caspase-8 and mitochondria-mediated cell death in phytosphingosine-treated human cancer cells'', J Biol Chem, 278: 50624-34.
Patel, S. G., and J. P. Shah. 2005. ''TNM staging of cancers of the head and neck: striving for uniformity among diversity'', CA Cancer J Clin, 55: 242-58; quiz 61-2, 64.
Pearson, G., F. Robinson, T. Beers Gibson, B. E. Xu, M. Karandikar, K. Berman, and M. H. Cobb. 2001. ''Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions'', Endocr Rev, 22: 153-83.
Petiti, J., V. Rosso, M. Lo Iacono, C. Panuzzo, C. Calabrese, E. Signorino, L. Pironi, A. Cartella, E. Bracco, B. Pergolizzi, T. Beltramo, C. Fava, and D. Cilloni. 2019. ''Curcumin induces apoptosis in JAK2-mutated cells by the inhibition of JAK2/STAT and mTORC1 pathways'', J Cell Mol Med.
Prasad, S., and B. B. Aggarwal. 2011. ''Turmeric, the Golden Spice: From Traditional Medicine to Modern Medicine.'' in nd, I. F. F. Benzie and S. Wachtel-Galor (eds.), Herbal Medicine: Biomolecular and Clinical Aspects (CRC Press/Taylor & Francis Llc.: Boca Raton (FL)).
Puthalakath, H., D. C. Huang, L. A. O''Reilly, S. M. King, and A. Strasser. 1999. ''The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex'', Mol Cell, 3: 287-96.
Raman, M., W. Chen, and M. H. Cobb. 2007. ''Differential regulation and properties of MAPKs'', Oncogene, 26: 3100-12.
Reidy, J., E. McHugh, and L. F. Stassen. 2011. ''A review of the relationship between alcohol and oral cancer'', Surgeon, 9: 278-83. Rivera, C. 2015. ''Essentials of oral cancer'', Int J Clin Exp Pathol, 8: 11884- 94.
Rouse, J., P. Cohen, S. Trigon, M. Morange, A. Alonso-Llamazares, D. Zamanillo, T. Hunt, and A. R. Nebreda. 1994. ''A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins'', Cell, 78: 1027-37.
Salehi, B., Z. Stojanovic-Radic, J. Matejic, M. Sharifi-Rad, N. V. Anil Kumar, N. Martins, and J. Sharifi-Rad. 2019. ''The therapeutic potential of curcumin: A review of clinical trials'', Eur J Med Chem, 163: 527-45.
Sandur, S. K., M. K. Pandey, B. Sung, K. S. Ahn, A. Murakami, G. Sethi, P. Limtrakul, V. Badmaev, and B. B. Aggarwal. 2007. ''Curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and turmerones differentially regulate anti-inflammatory and antiproliferative responses through a ROS-independent mechanism'', Carcinogenesis, 28: 1765-73.
Sarkar, D., Z. Z. Su, I. V. Lebedeva, M. Sauane, R. V. Gopalkrishnan, K. Valerie, P. Dent, and P. B. Fisher. 2002. ''mda-7 (IL-24) Mediates selective apoptosis in human melanoma cells by inducing the coordinated overexpression of the GADD family of genes by means of p38 MAPK'', Proc Natl Acad Sci U S A, 99: 10054-9.
Schneider, C., O. N. Gordon, R. L. Edwards, and P. B. Luis. 2015. ''Degradation of Curcumin: From Mechanism to Biological Implications'', J Agric Food Chem, 63: 7606-14.
Schroeter, H., C. S. Boyd, R. Ahmed, J. P. Spencer, R. F. Duncan, C. Rice- Evans, and E. Cadenas. 2003. ''c-Jun N-terminal kinase (JNK) mediated modulation of brain mitochondria function: new target proteins for JNK signalling in mitochondrion-dependent apoptosis'', Biochem J, 372: 359-69.
Schweyer, S., A. Soruri, O. Meschter, A. Heintze, F. Zschunke, N. Miosge, P. Thelen, T. Schlott, H. J. Radzun, and A. Fayyazi. 2004. ''Cisplatininduced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation'', Br J Cancer, 91: 589-98.
Scully, C., and J. Bagan. 2009. ''Oral squamous cell carcinoma overview'', Oral Oncol, 45: 301-8.
Shalini, S., L. Dorstyn, S. Dawar, and S. Kumar. 2015. ''Old, new and emerging functions of caspases'', Cell Death Differ, 22: 526-39.
Shi, L., and G. Sun. 2015. ''Low-Dose DMC Significantly Enhances the Effect of TMZ on Glioma Cells by Targeting Multiple Signaling Pathways Both In Vivo and In Vitro'', Neuromolecular Med, 17: 431- 42.
Sikora, E., A. Bielak-Zmijewska, A. Magalska, K. Piwocka, G. Mosieniak, M. Kalinowska, P. Widlak, I. A. Cymerman, and J. M. Bujnicki. 2006. ''Curcumin induces caspase-3-dependent apoptotic pathway but inhibits DNA fragmentation factor 40/caspase-activated DNase endonuclease in human Jurkat cells'', Mol Cancer Ther, 5: 927-34.
Stecca, B., and E. Rovida. 2019. ''Impact of ERK5 on the Hallmarks of Cancer'', Int J Mol Sci, 20.
Strimpakos, A. S., and R. A. Sharma. 2008. ''Curcumin: preventive and therapeutic properties in laboratory studies and clinical trials'', Antioxid Redox Signal, 10: 511-45.
Tang, D., D. Wu, A. Hirao, J. M. Lahti, L. Liu, B. Mazza, V. J. Kidd, T. W. Mak, and A. J. Ingram. 2002. ''ERK activation mediates cell cycle arrest and apoptosis after DNA damage independently of p53'', J Biol Chem, 277: 12710-7.
Turjanski, A. G., J. P. Vaque, and J. S. Gutkind. 2007. ''MAP kinases and the control of nuclear events'', Oncogene, 26: 3240-53.
Vyas, A., P. Dandawate, S. Padhye, A. Ahmad, and F. Sarkar. 2013. ''Perspectives on new synthetic curcumin analogs and their potential anticancer properties'', Curr Pharm Des, 19: 2047-69.

Wada, T., and J. M. Penninger. 2004. ''Mitogen-activated protein kinases in apoptosis regulation'', Oncogene, 23: 2838-49.
Wang, H., T. O. Khor, L. Shu, Z. Y. Su, F. Fuentes, J. H. Lee, and A. N. Kong. 2012. ''Plants vs. cancer: a review on natural phytochemicals in preventing and treating cancers and their druggability'', Anticancer Agents Med Chem, 12: 1281-305.
Weston, C. R., and R. J. Davis. 2002. ''The JNK signal transduction pathway'', Curr Opin Genet Dev, 12: 14-21.
Widmann, C., S. Gibson, M. B. Jarpe, and G. L. Johnson. 1999. ''Mitogenactivated protein kinase: conservation of a three-kinase module from yeast to human'', Physiol Rev, 79: 143-80.
Witsch, E., M. Sela, and Y. Yarden. 2010. ''Roles for growth factors in cancer progression'', Physiology (Bethesda), 25: 85-101.
Yete, S., W. D''Souza, and D. Saranath. 2018. ''High-Risk Human Papillomavirus in Oral Cancer: Clinical Implications'', Oncology, 94: 133-41.
Zahedpanah, M., J. S. Takanlu, M. Nikbakht, F. Rad, F. Farhid, S. A. Mousavi, S. Rad, H. K. Fumani, S. M. A. Hosseini Rad, and S. Mohammadi. 2019. ''Microvesicles of osteoblasts modulate bone marrow mesenchymal stem cell-induced apoptosis to curcumin in myeloid leukemia cells'', J Cell Physiol.
Zarubin, T., and J. Han. 2005. ''Activation and signaling of the p38 MAP kinase pathway'', Cell Res, 15: 11-8.
Zhang, X., L. C. Li, and S. Mao. 2014. ''Nanosuspensions of poorly water soluble drugs prepared by top-down technologies'', Curr Pharm Des, 20: 388-407.
Zhu, M., Z. Zheng, J. Huang, X. Ma, C. Huang, R. Wu, X. Li, Z. Liang, F. Deng, J. Wu, S. Geng, C. Xie, and C. Zhong. 2019. ''Modulation of miR-34a in curcumin-induced antiproliferation of prostate cancer cells'', J Cell Biochem.
Zhuang, S., J. T. Demirs, and I. E. Kochevar. 2000. ''p38 mitogen-activated protein kinase mediates bid cleavage, mitochondrial dysfunction, and caspase-3 activation during apoptosis induced by singlet oxygen but not by hydrogen peroxide'', J Biol Chem, 275: 25939-48.