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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 許麗卿 | |
| dc.contributor.author | Po-Chia Su | en |
| dc.contributor.author | 蘇柏嘉 | zh_TW |
| dc.date.accessioned | 2021-06-17T02:43:02Z | - |
| dc.date.available | 2022-09-14 | |
| dc.date.copyright | 2017-09-14 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-08-16 | |
| dc.identifier.citation | 1. Hennessy BT, Coleman RL and Markman M. Ovarian cancer. Lancet. 2009; 374:1371-1382.
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Pathology. 2007; 39:305-318. 8. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2015-2016.pdf. 9. Dual HER2 Blockade Helps Prevent Breast Cancer Return. Cancer Discov. 2017; 7:790. 10. Steeg PS. Targeting metastasis. Nat Rev Cancer. 2016; 16:201-218. 11. Geiger TR and Peeper DS. Metastasis mechanisms. Biochim Biophys Acta. 2009; 1796:293-308. 12. Kalluri R and Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009; 119:1420-1428. 13. Lamouille S, Xu J and Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014; 15:178-196. 14. Zeisberg M and Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 2009; 119:1429-1437. 15. Stemmer V, de Craene B, Berx G and Behrens J. Snail promotes Wnt target gene expression and interacts with beta-catenin. Oncogene. 2008; 27:5075-5080. 16. Xu W, Yang Z and Lu N. A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition. Cell Adh Migr. 2015; 9:317-324. 17. Shaw RJ and Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006; 441:424-430. 18. Hennessy BT, Smith DL, Ram PT, Lu Y and Mills GB. Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery. Nat Rev Drug Discov. 2005; 4:988-1004. 19. Medici D, Hay ED and Olsen BR. Snail and Slug promote epithelial-mesenchymal transition through beta-catenin-T-cell factor-4-dependent expression of transforming growth factor-beta3. Mol Biol Cell. 2008; 19:4875-4887. 20. Montero JC, Chen X, Ocana A and Pandiella A. Predominance of mTORC1 over mTORC2 in the regulation of proliferation of ovarian cancer cells: therapeutic implications. Mol Cancer Ther. 2012; 11:1342-1352. 21. Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, Botero ML, Llonch E, Atzori F, Di Cosimo S, Maira M, Garcia-Echeverria C, Parra JL, Arribas J and Baselga J. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008; 68:8022-8030. 22. ClinicalTrials.gov Identifier: NCT01495247. 23. Jordan MA and Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer. 2004; 4:253-265. 24. Giannakakou P, Sackett D and Fojo T. Tubulin/microtubules: still a promising target for new chemotherapeutic agents. J Natl Cancer Inst. 2000; 92:182-183. 25. Dumontet C and Jordan MA. Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat Rev Drug Discov. 2010; 9:790-803. 26. Anderson HJ, Coleman JE, Andersen RJ and Roberge M. Cytotoxic peptides hemiasterlin, hemiasterlin A and hemiasterlin B induce mitotic arrest and abnormal spindle formation. Cancer Chemother Pharmacol. 1997; 39:223-226. 27. Hsu LC, Durrant DE, Huang CC, Chi NW, Baruchello R, Rondanin R, Rullo C, Marchetti P, Grisolia G, Simoni D and Lee RM. Development of hemiasterlin derivatives as potential anticancer agents that inhibit tubulin polymerization and synergize with a stilbene tubulin inhibitor. Invest New Drugs. 2012; 30:1379-1388. 28. Lai WT, Cheng KL, Baruchello R, Rondanin R, Marchetti P, Simoni D, Lee RM, Guh JH and Hsu LC. Hemiasterlin derivative (R)(S)(S)-BF65 and Akt inhibitor MK-2206 synergistically inhibit SKOV3 ovarian cancer cell growth. Biochem Pharmacol. 2016; 113:12-23. 29. Wu Y and Zhou BP. Snail: More than EMT. Cell Adh Migr. 2010; 4:199-203. 30. Oishi T, Itamochi H, Kudoh A, Nonaka M, Kato M, Nishimura M, Oumi N, Sato S, Naniwa J, Sato S, Shimada M, Kigawa J and Harada T. The PI3K/mTOR dual inhibitor NVP-BEZ235 reduces the growth of ovarian clear cell carcinoma. Oncol Rep. 2014; 32:553-558. 31. Kuger S, Corek E, Polat B, Kammerer U, Flentje M and Djuzenova CS. Novel PI3K and mTOR Inhibitor NVP-BEZ235 Radiosensitizes Breast Cancer Cell Lines under Normoxic and Hypoxic Conditions. Breast Cancer (Auckl). 2014; 8:39-49. 32. Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J and Garcia De Herreros A. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000; 2:84-89. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/68936 | - |
| dc.description.abstract | 癌細胞由原發性腫瘤擴散至不相鄰的其他器官稱之為腫瘤轉移。而上皮間質轉換 (Epithelial–mesenchymal transition, EMT) 是癌細胞轉移的早期步驟，其作用使得癌細胞間的聯繫鬆散，進一步誘發癌細胞遷移和侵入至其他器官。腫瘤轉移是造成癌症治療失敗和病患死亡的常見因素，因此，抑制腫瘤轉移被視為癌症治療一項重要的議題。
在女性中，卵巢癌與乳癌是排名前兩位致死率最高的癌症，在此類癌症的治療上，合併藥物治療的概念扮演了重要的角色，合併治療不僅能夠減少藥物的毒性和所造成的副作用，甚至可以增加對抗癌細胞的效果。在本研究中，我們利用傷口癒合(畫痕法)、 transwell 遷移和侵入實驗發現海綿胜肽成分hemiasterlin的全合成抗微管劑 (R)(S)(S)-BF65 能夠提升PI3K/mTOR 雙重抑制劑NVP-BEZ235在癌細胞中造成抑制移動能力的效果，而此效果同時在人類卵巢癌細胞株SKOV3和人類乳癌細胞株 MDA-MB-231被觀察到。更進一步發現，合併使用 NVP-BEZ235 和 (R)(S)(S)-BF65 能夠調控EMT相關的蛋白表現量，例如：E-cadherin、Slug、Snail等，這些蛋白表現量變化也被證明參與在PI3K/AKT/GSK3 的一系列訊號路徑中。 總而言之， NVP-BEZ235 和 (R)(S)(S)-BF65 合併使用在抑制癌細胞移行的能力上顯現出協同的效果。因此，這兩種藥物合併使用可視為對於抑制癌細胞轉移的潛在策略。 | zh_TW |
| dc.description.abstract | Tumor metastasis is the spread of tumor cells from primary tumor site to another organ which is not directly connected. Epithelial–mesenchymal transition (EMT), an early step of cancer metastasis, allows cancer cells lose connections with neighboring cells, thereby inducing cellular migration and invasion. Metastasis has been a big issue to cancer therapy and causes therapeutic failure and the death of patients. Therefore, inhibiting cancer metastasis is a major concern of cancer treatment.
Ovarian cancer and breast cancer are the top two lethal cancers among woman. The concept of combination treatment plays an essential role in cancer therapy to reduce the toxicity and side effects, and to enhance the anti-cancer effect. In this study, we found that (R)(S)(S)-BF65 could enhance cell motility inhibition effect of NVP-BEZ235, a PI3K/mTOR dual inhibitor, using wound healing migration, transwell migration and invasion assays, and this effect appeared in both human ovarian cancer cell line SKOV3 and human breast cancer cell line MDA-MB-231. Moreover, the combination of NVP-BEZ235 and (R)(S)(S)-BF65 regulated EMT associated biomarkers, such as E-cadherin, Slug and Snail, which are involved in the PI3K/AKT/GSK3beta signaling pathway. In conclusion, NVP-BEZ235 and (R)(S)(S)-BF65 synergistically inhibit migration ability of cancer cells. Thus, this combination treatment may be a potential strategy against cancer metastasis. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T02:43:02Z (GMT). No. of bitstreams: 1 ntu-106-R04423014-1.pdf: 74189741 bytes, checksum: e82dbd18d6464308b6e5b1a133086b4d (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | Certification by the Oral Defense Committee I
Acknowledgements II Chinese abstract III Abstract IV Table of Contents V List of Figures VIII List of Tables XI Chapter 1 Introduction 1 1.1 Ovarian cancer 1 1.2 Breast cancer 2 1.3 Cancer metastasis 3 1.3.1 Epithelial–mesenchymal transition (EMT) 4 1.3.2 The role of the PI3K/AKT/mTOR pathway in cancer metastasis 5 1.4 The PI3K/mTOR dual inhibitor --- NVP-BEZ235 5 1.5 Anti-microtubule agents --- Hemiasterlins 6 Chapter 2 Research significance and objectives 17 Chapter 3 Materials and methods 18 3.1 Chemicals and reagents 18 3.2 Cell culture and drug treatment 18 3.3 Cell viability assay 19 3.4 Wound healing migration assay 19 3.5 Transwell migration and invasion assays 20 3.6 Western blot analysis 21 3.7 Quantitative real-time PCR 22 3.8 Transfection 23 3.9 Statistical analysis 23 Chapter 4 Results 24 4.1 (R)(S)(S)-BF65 enhances the growth inhibitory effect of NVP-BEZ235 in both SKOV3 and MDA-MB-231 cancer cell lines 24 4.2 (R)(S)(S)-BF65 enhances the inhibition of cell migration and cell invasion by NVP-BEZ235 without affecting cell viability 25 4.2.1 Selection of proper drug concentrations to test cell motility using wound healing migration assay 25 4.2.2 Determination of the drug-induced cell migration inhibitory effects using transwell migration assay 26 4.2.3 The drugs inhibited not only the cell migration but also cell invasion in vitro 27 4.2.4 Cytotoxicity of the drugs is not the main cause of cell motility inhibition 27 4.3 NVP-BEZ235 and (R)(S)(S)-BF65 affect the expression of EMT-associated biomarkers 28 Chapter 5 Discussion 47 5.1 The combination treatment of NVP-BEZ-235 and (R)(S)(S)-BF65 displays slight synergistic effect on cytotoxicity but obvious synergistic effect on cell motility inhibition in both SKOV3 and MDA-MB-231 cancer cell lines 47 5.2 Blocking the PI3K/AKT/mTOR pathway leads to GSK3beta activation and further suppression of the downstream mesenchymal markers, beta-catenin, Slug and Snail 48 5.3 The role of Snail involved in NVP-BEZ235 and (R)(S)(S)-BF65 induced cell motility inhibition 48 Chapter 6 Conclusion 53 References 54 | |
| dc.language.iso | en | |
| dc.subject | 乳癌細胞 | zh_TW |
| dc.subject | 卵巢癌細胞 | zh_TW |
| dc.subject | hemiasterlin抗微管劑 (R)(S)(S)-BF65 | zh_TW |
| dc.subject | 腫瘤轉移 | zh_TW |
| dc.subject | PI3K/mTOR 雙重抑制劑 NVP-BEZ235 | zh_TW |
| dc.subject | hemiasterlin (R)(S)(S)-BF65 | en |
| dc.subject | epithelial–mesenchymal transition (EMT) | en |
| dc.subject | ovarian cancer | en |
| dc.subject | breast cancer | en |
| dc.subject | anti-microtutubl | en |
| dc.subject | tumor metastasis | en |
| dc.subject | PI3K/mTOR dual inhibitor NVP-BEZ235 | en |
| dc.title | Hemiasterlin (R)(S)(S)-BF65增強PI3K/AKT抑制劑抑制細胞遷移的效果 | zh_TW |
| dc.title | Hemiasterlin derivative (R)(S)(S)-BF65 enhances the cell migration inhibitory effect of PI3K/AKT/mTOR inhibitor | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 孔繁璐,蘇瑀,顧記華 | |
| dc.subject.keyword | 腫瘤轉移,卵巢癌細胞,乳癌細胞,hemiasterlin抗微管劑 (R)(S)(S)-BF65,PI3K/mTOR 雙重抑制劑 NVP-BEZ235, | zh_TW |
| dc.subject.keyword | tumor metastasis,epithelial–mesenchymal transition (EMT),ovarian cancer,breast cancer,anti-microtutubl,hemiasterlin (R)(S)(S)-BF65,PI3K/mTOR dual inhibitor NVP-BEZ235, | en |
| dc.relation.page | 57 | |
| dc.identifier.doi | 10.6342/NTU201703470 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2017-08-16 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥學研究所 | zh_TW |
| Appears in Collections: | 藥學系 | |
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