In vitro anti-cancer properties of bisindole alkaloids from Tabernaemontana corymbosa and Alstonia penangiana against human colon cancer cells / Tan Chun Hoe
The natural product is a continuing source for the discovery of potential anti-cancer drugs. Two iboga-vobasine bisindole alkaloids, namely 16'-decarbomethoxyvoacamine (1) and its 19,20-dihydro derivative, 16'-decarbomethoxydihydrovoacamine (2) were previously isolated from the stem-bark e...
Saved in:
| Main Author: | |
|---|---|
| Format: | Thesis |
| Published: |
2022
|
| Subjects: | |
| Online Access: | http://studentsrepo.um.edu.my/15195/2/Tan_Chun_Hoe.pdf http://studentsrepo.um.edu.my/15195/1/Tan_Chun_Hoe.pdf http://studentsrepo.um.edu.my/15195/ |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1831436572732424192 |
|---|---|
| author | Tan , Chun Hoe |
| author_facet | Tan , Chun Hoe |
| author_sort | Tan , Chun Hoe |
| building | UM Library |
| collection | Institutional Repository |
| content_provider | Universiti Malaya |
| content_source | UM Student Repository |
| continent | Asia |
| country | Malaysia |
| description | The natural product is a continuing source for the discovery of potential anti-cancer drugs. Two iboga-vobasine bisindole alkaloids, namely 16'-decarbomethoxyvoacamine (1) and its 19,20-dihydro derivative, 16'-decarbomethoxydihydrovoacamine (2) were previously isolated from the stem-bark extract of Tabernaemontana corymbosa. In addition, a macroline-akuammiline bisindole angustilongine A (3) and a linearly-fused macroline-sarpagine bisindole, angustilongine M (4) were isolated from the leaf and stem-bark extract of Alstonia penangiana, respectively. The preliminary cytotoxicity screening demonstrated that bisindoles 1–4 exhibited strong growth inhibitory effects against a wide array of human cancer cell lines, predominantly against colorectal cancer (CRC). Herein, the antiproliferative activity and underlying mechanisms of the bisindoles in human colorectal adenocarcinoma HT-29 and carcinoma HCT 116 were further investigated. The studies demonstrated that 1–4 exhibited pronounced antiproliferative activities against HT-29 and HCT 116 cells in both dose- and time-dependent manners without significant cytotoxicity to normal human colon fibroblast (CCD-18Co). Owing to its highest antiproliferative activity and selectivity in both CRC cell lines, 2 was chosen for the subsequent studies. Brief treatment with 2 for 24 h potently inhibited the colonies formation of the CRC cells and the effect was suggested to be long-term and irreversible. Bisindole 2 inhibited the formation of HT-29 spheroids (tumor-like cell aggregates) in 3D experiments in a dose-dependent manner. In HT-29, the binding of 2 at the Taxol- binding site of β-tubulin contributed to the generation of ROS, causing DNA damage. Consequently, three signaling pathways, i.e., JNK/p38, p21Cip1/Rb/E2F, and p21Cip1/Chk1 were activated. In contrast, treatment with 2 enhanced the drug metabolism in HCT 116 through the induction of cytochrome P450 enzymes, subsequently leading to the oxidative damage to DNA and activation of the GADD45/p21Cip1 pathway. In both CRC cell lines, the activation of their respective pathways resulted in cell cycle arrest, induction of caspase-dependent mitochondrial apoptosis, and inhibition of metastasis (in HCT 116 only). In addition, treatment with 2 has reversed the 5-fluorouracil (5-FU) resistance of HCT 116-5FUR (5-fluorouracil-resistant HCT 116 derivative cell line) in a synergic manner with 5-FU. Lastly, the calculated physiochemical properties of 2 suggested that it could be a suitable candidate to be used as an in vivo model due to its high bioavailability, non-toxicity, and good drug-likeness score.
|
| format | Thesis |
| id | my.um.stud-15195 |
| institution | Universiti Malaya |
| publishDate | 2022 |
| record_format | eprints |
| spelling | my.um.stud-151952024-11-25T22:52:36Z In vitro anti-cancer properties of bisindole alkaloids from Tabernaemontana corymbosa and Alstonia penangiana against human colon cancer cells / Tan Chun Hoe Tan , Chun Hoe Q Science (General) QH301 Biology The natural product is a continuing source for the discovery of potential anti-cancer drugs. Two iboga-vobasine bisindole alkaloids, namely 16'-decarbomethoxyvoacamine (1) and its 19,20-dihydro derivative, 16'-decarbomethoxydihydrovoacamine (2) were previously isolated from the stem-bark extract of Tabernaemontana corymbosa. In addition, a macroline-akuammiline bisindole angustilongine A (3) and a linearly-fused macroline-sarpagine bisindole, angustilongine M (4) were isolated from the leaf and stem-bark extract of Alstonia penangiana, respectively. The preliminary cytotoxicity screening demonstrated that bisindoles 1–4 exhibited strong growth inhibitory effects against a wide array of human cancer cell lines, predominantly against colorectal cancer (CRC). Herein, the antiproliferative activity and underlying mechanisms of the bisindoles in human colorectal adenocarcinoma HT-29 and carcinoma HCT 116 were further investigated. The studies demonstrated that 1–4 exhibited pronounced antiproliferative activities against HT-29 and HCT 116 cells in both dose- and time-dependent manners without significant cytotoxicity to normal human colon fibroblast (CCD-18Co). Owing to its highest antiproliferative activity and selectivity in both CRC cell lines, 2 was chosen for the subsequent studies. Brief treatment with 2 for 24 h potently inhibited the colonies formation of the CRC cells and the effect was suggested to be long-term and irreversible. Bisindole 2 inhibited the formation of HT-29 spheroids (tumor-like cell aggregates) in 3D experiments in a dose-dependent manner. In HT-29, the binding of 2 at the Taxol- binding site of β-tubulin contributed to the generation of ROS, causing DNA damage. Consequently, three signaling pathways, i.e., JNK/p38, p21Cip1/Rb/E2F, and p21Cip1/Chk1 were activated. In contrast, treatment with 2 enhanced the drug metabolism in HCT 116 through the induction of cytochrome P450 enzymes, subsequently leading to the oxidative damage to DNA and activation of the GADD45/p21Cip1 pathway. In both CRC cell lines, the activation of their respective pathways resulted in cell cycle arrest, induction of caspase-dependent mitochondrial apoptosis, and inhibition of metastasis (in HCT 116 only). In addition, treatment with 2 has reversed the 5-fluorouracil (5-FU) resistance of HCT 116-5FUR (5-fluorouracil-resistant HCT 116 derivative cell line) in a synergic manner with 5-FU. Lastly, the calculated physiochemical properties of 2 suggested that it could be a suitable candidate to be used as an in vivo model due to its high bioavailability, non-toxicity, and good drug-likeness score. 2022-01 Thesis NonPeerReviewed application/pdf http://studentsrepo.um.edu.my/15195/2/Tan_Chun_Hoe.pdf application/pdf http://studentsrepo.um.edu.my/15195/1/Tan_Chun_Hoe.pdf Tan , Chun Hoe (2022) In vitro anti-cancer properties of bisindole alkaloids from Tabernaemontana corymbosa and Alstonia penangiana against human colon cancer cells / Tan Chun Hoe. PhD thesis, Universiti Malaya. http://studentsrepo.um.edu.my/15195/ |
| spellingShingle | Q Science (General) QH301 Biology Tan , Chun Hoe In vitro anti-cancer properties of bisindole alkaloids from Tabernaemontana corymbosa and Alstonia penangiana against human colon cancer cells / Tan Chun Hoe |
| title | In vitro anti-cancer properties of bisindole alkaloids from Tabernaemontana corymbosa and Alstonia penangiana against human colon cancer cells / Tan Chun Hoe |
| title_full | In vitro anti-cancer properties of bisindole alkaloids from Tabernaemontana corymbosa and Alstonia penangiana against human colon cancer cells / Tan Chun Hoe |
| title_fullStr | In vitro anti-cancer properties of bisindole alkaloids from Tabernaemontana corymbosa and Alstonia penangiana against human colon cancer cells / Tan Chun Hoe |
| title_full_unstemmed | In vitro anti-cancer properties of bisindole alkaloids from Tabernaemontana corymbosa and Alstonia penangiana against human colon cancer cells / Tan Chun Hoe |
| title_short | In vitro anti-cancer properties of bisindole alkaloids from Tabernaemontana corymbosa and Alstonia penangiana against human colon cancer cells / Tan Chun Hoe |
| title_sort | in vitro anti-cancer properties of bisindole alkaloids from tabernaemontana corymbosa and alstonia penangiana against human colon cancer cells / tan chun hoe |
| topic | Q Science (General) QH301 Biology |
| url | http://studentsrepo.um.edu.my/15195/2/Tan_Chun_Hoe.pdf http://studentsrepo.um.edu.my/15195/1/Tan_Chun_Hoe.pdf http://studentsrepo.um.edu.my/15195/ |
| url_provider | http://studentsrepo.um.edu.my/ |