Colorectal cancer is the second leading cause of cancer-related mortality in Hong Kong and lack of selectivity has limited the success of conventional chemotherapy. Given the recent interest in the anti-cancer effects of traditional Chinese medicine (TCM), there are two approaches to studying its bioactivity: as a mixture of ingredients or as single compounds. The objective of the present study is to examine the anti-tumor effects of Angelicae Sinensis Radix (DG) and Garcinia hanburyi resin (TH) using both approaches, respectively, as they are traditionally used to treat inflammation. In the present study, their anti-cancer effects and the mechanisms of actions were examined for the development of potential novel chemotherapeutic drugs for colon cancer since inflammation is a predisposing factor for colon cancer. / DG extract and its three main bioactive phtbalides: n-butylidenephthalide, senkyunolide A and z-ligustilide (LGT), were found to be cytotoxic to HT-29 cells with IC50 values (24 h) of 20.70 +/- 0.85, 72.51 +/- 8.65, 18.74 +/- 1.14 and 41.98 +/- 3.64 mug/ml, respectively. The results evidenced that LGT induced G0/G 1 arrest and apoptosis, triggering cleavage of PARP, pro-caspases-3, -8 and -9 and nuclear fragmentation. LGT and cisplatin synergistically reduced the viability of HT-29 cells. More interestingly, DG extract was more potent than individual phthalides, suggesting that there are other bioactive components and/or synergistic interactions. / Individual compounds purified from TH were investigated because gambogic acid isolated from this herb has been used clinically to treat cancer, 30-Epicambogin (EPC) and guttiferone K (GUTK) showed the highest cytotoxic selectivity and potency on HT-29 cells among 15 isolated compounds. IC50 values (24 h) for EPC and GUTK in HT-29 cells were 5.36+/-0.25 and 5.39+/-0.22 muM, respectively, and both induced G0/G1 arrest by down-regulation of cyclins D1, D3, CDK4 and CDK6, while up-regulation of p21Waf1/CiP1 and p27KiP1. Both compounds triggered the activation of caspases-3, -8 and -9 in apoptosis. The in vivo anti-tumor effects of GUTK were further investigated by using a subcutaneous Colon-26 mouse tumor model. GUTK (10 mg/kg i.p.) reduced tumor volume by 33.6% and potentiated the anti-tumor effects of 5-fluorouracil when administered concurrently. / Our findings revealed that DG rather than individual phthalides, is worthy for further study as a potential anti-cancer drug, due to the synergistic interactions among multi-components in the herb. On the other hand, EPC and GUTK, isolated from TH have potential to be developed as novel anti-tumor candidates for combination use with 5-fluorouracil. The results strongly support the use of different approaches to study TCM for chemotherapy, according to its traditional and empirical use. / Subsequently, the anti-proliferative effects of DG and Chuanxiong Rhizoma (CX) extracts and mixtures containing three phthalides in the proportions similar to their presence in both extracts were examined, since CX also contains the same phthalides, but in different proportions. DG extract was significantly more potent than its corresponding phthalide mixture to inhibit cancer cell proliferation and synergistic interaction was observed among the phthalides and other bioactive components, while the phthalides in CX extract interacted antagonistically with other components. / Kan, Lai Ting Winnie. / Adviser: Ge Lin. / Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 267-311). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_344670 |
| Date | January 2010 |
| Contributors | Kan, Lai Ting Winnie., Chinese University of Hong Kong Graduate School. Division of Pharmacology. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, theses |
| Format | electronic resource, microform, microfiche, 1 online resource (xvi, 311 leaves : ill.) |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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