The Bisindole Alkaloids Angustilongines M and A from Alstonia penangiana Induce Mitochondrial Apoptosis and G0/G1
Cell Cycle Arrest in HT-29 Cells through Promotion of Tubulin Polymerization
posted on 2021-04-19, 17:16authored byChun-Hoe Tan, Joanne Soon-Yee Yeap, Siew-Huah Lim, Yun-Yee Low, Kae-Shin Sim, Toh-Seok Kam
A new linearly fused macroline-sarpagine bisindole, angustilongine
M (1), was isolated from the methanolic extract of Alstonia penangiana. The structure of the alkaloid was elucidated
based on analysis of the spectroscopic data, and its biological activity
was evaluated together with another previously reported macroline-akuammiline
bisindole from the same plant, angustilongine A (2).
Compounds 1 and 2 showed pronounced in vitro
growth inhibitory activity against a wide panel of human cancer cell
lines. In particular, the two compounds showed potent and selective
antiproliferative activity against HT-29 cells, as well as strong
growth inhibitory effects against HT-29 spheroids. Cell death mechanistic
studies revealed that the compounds induced mitochondrial apoptosis
and G0/G1 cell cycle arrest in HT-29 cells in a time-dependent manner,
while in vitro tubulin polymerization assays and molecular docking
analysis showed that the compounds are microtubule-stabilizing agents,
which are predicted to bind at the β-tubulin subunit at the
Taxol-binding site.