Planta Med 2022; 88(14): 1325-1340
DOI: 10.1055/a-1755-5605
Biological and Pharmacological Activity
Original Papers

Antiproliferative and Microtubule-stabilizing Activities of Two Iboga-vobasine Bisindoles Alkaloids from Tabernaemontana corymbosa in Colorectal Adenocarcinoma HT-29 Cells

Authors

  • Chun Hoe Tan

    1   Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Jalan Profesor Diraja Ungku Aziz, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia
  • Dawn Su Yin Sim

    2   Department of Chemistry, Faculty of Science, Universiti Malaya, Jalan Profesor Diraja Ungku Aziz, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia
  • Siew Huah Lim

    2   Department of Chemistry, Faculty of Science, Universiti Malaya, Jalan Profesor Diraja Ungku Aziz, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia
  • Taznim Begam Mohd Mohidin

    1   Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Jalan Profesor Diraja Ungku Aziz, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia
  • Gokula Mohan

    1   Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Jalan Profesor Diraja Ungku Aziz, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia
  • Yun Yee Low

    2   Department of Chemistry, Faculty of Science, Universiti Malaya, Jalan Profesor Diraja Ungku Aziz, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia
  • Toh Seok Kam

    2   Department of Chemistry, Faculty of Science, Universiti Malaya, Jalan Profesor Diraja Ungku Aziz, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia
  • Kae Shin Sim

    1   Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Jalan Profesor Diraja Ungku Aziz, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia

Gefördert durch: Ministry of Education, Malaysia FRGS/1/2019/STG01/UM/02/23 (FP100-2019A)
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Abstract

Two iboga-vobasine bisindoles, 16′-decarbomethoxyvoacamine (1) and its 19,20-dihydro derivative, 16′-decarbomethoxydihydrovoacamine (2) from Tabernaemontana corymbosa exhibited potent cytotoxicity against the human colorectal adenocarcinoma HT-29 cells in our previous studies. Bisindoles 1 and 2 selectively inhibited the growth of HT-29 cells without significant cytotoxicity to normal human colon fibroblasts CCD-18Co. Treatment with bisindoles 1 and 2 suppressed the formation of HT-29 colonies via G0/G1 cell cycle arrest and induction of mitochondrial apoptosis. Owing to its higher antiproliferative activity, bisindole 2 was chosen for the subsequent studies. Bisindole 2 inhibited the formation of HT-29 spheroids (tumor-like cell aggregates) in 3D experiments in a dose-dependent manner, while an in vitro tubulin polymerization assay and molecular docking analysis showed that bisindole 2 is a microtubule-stabilizing agent which is predicted to bind at the β-tubulin subunit at the taxol-binding site. The binding resulted in the generation of ROS, which consequently activated the oxidative stress-related cell cycle arrest and apoptotic pathways, viz., JNK/p38, p21Cip1/Chk1, and p21Cip1/Rb/E2F, as shown by microarray profiling.

Supporting Information



Publikationsverlauf

Eingereicht: 03. Dezember 2021

Angenommen nach Revision: 28. Januar 2022

Accepted Manuscript online:
31. Januar 2022

Artikel online veröffentlicht:
17. März 2022

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