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 (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.

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Abstract

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.

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