Download PDF
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

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
› Author AffiliationsSupported by: Ministry of Education, Malaysia FRGS/1/2019/STG01/UM/02/23 (FP100-2019A)
› Further Information
    Permissions and Reprints

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.

Key words

Tabernaemontana corymbosa - Apocynaceae - 16′-Decarbomethoxyvoacamine - 16′-Decarbomethoxydihydrovoacamine - Apoptosis - G0/G1 phase arrest

Supporting Information

    Flow cytometric data, physiochemical properties of bisindoles 1 and 2, and list of primers are available as Supporting Information.

  • Supporting Information


Publication History

Received: 03 December 2021

Accepted after revision: 28 January 2022

Accepted Manuscript online:
31 January 2022

Article published online:
17 March 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet 2019; 394: 1467-1480
    CrossrefPubMedGoogle Scholar
  • 2 Tewari D, Rawat P, Singh PK. Adverse drug reactions of anticancer drugs derived from natural sources. Food Chem Toxicol 2019; 123: 522-535
    CrossrefPubMedGoogle Scholar
  • 3 Finch GL, Burns-Naas LA. Cancer Chemotherapeutic Agents. In: Wexler P. ed. Encyclopedia of Toxicology (Third Edition). Oxford: Academic Press; 2014: 630-641
    Google Scholar
  • 4 Cragg GM, Newman DJ. Natural Products as Sources of Anticancer Agents: Current Approaches and Perspectives. In: Natural Products as Source of Molecules with Therapeutic Potential. Cham: Springer; 2018: 309-331
    Google Scholar
  • 5 Butler MS. Natural products to drugs: Natural product-derived compounds in clinical trials. Nat Prod Rep 2008; 25: 475-516
    CrossrefPubMedGoogle Scholar
  • 6 Canta A, Chiorazzi A, Cavaletti G. Tubulin: a target for antineoplastic drugs into the cancer cells but also in the peripheral nervous system. Curr Med Chem 2009; 16: 1315-1324
    CrossrefPubMedGoogle Scholar
  • 7 Sim DSY, Teoh WY, Sim KS, Lim SH, Thomas NF, Low YY, Kam TS. Vobatensines A–F, cytotoxic iboga-vobasine bisindoles from Tabernaemontana corymbosa . J Nat Prod 2016; 79: 1048-1055
    CrossrefPubMedGoogle Scholar
  • 8 Braga RM, Leitáo Filho HF, Reist FDAM. 13C NMR analysis of alkaloids from Peschiera fuchsiaefolia . Phytochemistry 1984; 23: 175-178
    CrossrefPubMedGoogle Scholar
  • 9 Clivio P, Richard B, Deverre JR, Sevenet T, Zeches M, Le Men-Oliver L. Alkaloids from leaves and root bark of Ervatamia hirta . Phytochemistry 1991; 30: 3785-3792
    CrossrefPubMedGoogle Scholar
  • 10 Knox JR, Slobbe J. Indole alkaloids from Ervatamia orientalis. I. Isolation of alkaloids and structural identification of two dimers. Aust J Chem 1975; 28: 1813-1823
    CrossrefPubMedGoogle Scholar
  • 11 Tan CH, Sim DSY, Heng MP, Lim SH, Low YY, Kam TS, Sim KS. Evaluation of DNA binding and topoisomerase I inhibitory activities of 16′-decarbomethoxydihydrovoacamine from Tabernaemontana corymbosa . ChemistrySelect 2020; 5: 14839-14843
    CrossrefPubMedGoogle Scholar
  • 12 Desai S, Desai V, Shingade S. In vitro anti-cancer assay and apoptotic cell pathway of newly synthesized benzoxazole-N-heterocyclic hybrids as potent tyrosine kinase inhibitors. Bioorg Chem 2020; 94: 103382
    CrossrefPubMedGoogle Scholar
  • 13 Steinmetz MO, Prota AE. Microtubule-targeting agents: Strategies to hijack the cytoskeleton. Trends Cell Biol 2018; 28: 776-792
    CrossrefPubMedGoogle Scholar
  • 14 Lowe J, Li H, Downing KH, Nogales E. Refined structure of alpha beta-tubulin at 3.5 A resolution. J Mol Biol 2001; 313: 1045-1057
    CrossrefPubMedGoogle Scholar
  • 15 Rejhová A, Opattová A, Čumová A, Slíva D, Vodička P. Natural compounds and combination therapy in colorectal cancer treatment. Eur J Med Chem 2018; 144: 582-594
    CrossrefPubMedGoogle Scholar
  • 16 Sánchez-Martínez C, Lallena MJ, Sanfeliciano SG, de Dios A. Cyclin dependent kinase (CDK) inhibitors as anticancer drugs: Recent advances (2015–2019). Bioorg Med Chem Lett 2019; 29: 126637
    CrossrefPubMedGoogle Scholar
  • 17 Sherr CJ. The Pezcoller lecture: Cancer cell cycles revisited. Cancer Res 2000; 60: 3689
    PubMedGoogle Scholar
  • 18 Palmqvist R, Stenling R, Öberg Å, Landberg G. Expression of cyclin D1 and retinoblastoma protein in colorectal cancer. Eur J Cancer 1998; 34: 1575-1581
    CrossrefPubMedGoogle Scholar
  • 19 Fu Y, Kadioglu O, Wiench B, Wei Z, Gao C, Luo M, Gu C, Zu Y, Efferth T. Cell cycle arrest and induction of apoptosis by cajanin stilbene acid from Cajanus cajan in breast cancer cells. Phytomedicine 2015; 22: 462-468
    CrossrefPubMedGoogle Scholar
  • 20 Chen J, Shao B, Wang J, Shen Z, Liu H, Li S. Chlorpyrifos caused necroptosis via MAPK/NF-κB/TNF-α pathway in common carp (Cyprinus carpio L.) gills. Comp Biochem Physiol. Part C: Toxicol Pharmacol 2021; 249: 109126
    PubMedGoogle Scholar
  • 21 Al Mamun A, Mimi AA, Aziz MA, Zaeem M, Ahmed T, Munir F, Xiao J. Role of pyroptosis in cancer and its therapeutic regulation. Eur J Pharmacol 2021; 910: 174444 DOI: 10.1016/j.ejphar.2021.174444.
    CrossrefPubMedGoogle Scholar
  • 22 Mondal A, Gandhi A, Fimognari C, Atanasov AG, Bishayee A. Alkaloids for cancer prevention and therapy: Current progress and future perspectives. Eur J Pharmacol 2019; 858: 172472
    CrossrefPubMedGoogle Scholar
  • 23 Brancale A, Silvestri R. Indole, a core nucleus for potent inhibitors of tubulin polymerization. Med Res Rev 2007; 27: 209-238
    CrossrefPubMedGoogle Scholar
  • 24 Chiu WH, Luo SJ, Chen CL, Cheng JH, Hsieh CY, Wang CY, Huang WC, Su WC, Lin CF. Vinca alkaloids cause aberrant ROS-mediated JNK activation, Mcl-1 downregulation, DNA damage, mitochondrial dysfunction, and apoptosis in lung adenocarcinoma cells. Biochem Pharmacol 2012; 83: 1159-1171
    CrossrefPubMedGoogle Scholar
  • 25 Smedley CJ, Stanley PA, Qazzaz ME, Prota AE, Olieric N, Collins H, Eastman H, Barrow AS, Lim KH, Kam TS, Smith BJ, Duivenvoorden HM, Parker BS, Bradshaw TD, Steinmetz MO, Moses JE. Sustainable syntheses of (−)-jerantinines A & E and structural characterisation of the jerantinine-tubulin complex at the colchicine binding site. Sci Rep 2018; 8: 10617
    CrossrefPubMedGoogle Scholar
  • 26 Raja VJ, Lim KH, Leong CO, Kam TS, Bradshaw TD. Novel antitumour indole alkaloid, Jerantinine A, evokes potent G2/M cell cycle arrest targeting microtubules. Invest New Drugs 2014; 32: 838-850
    CrossrefPubMedGoogle Scholar
  • 27 Chen N, Guo D, Guo Y, Sun Y, Bi H, Ma X. Paclitaxel inhibits cell proliferation and collagen lattice contraction via TGF-β signaling pathway in human tenonʼs fibroblasts in vitro . Eur J Pharmacol 2016; 777: 33-40
    CrossrefPubMedGoogle Scholar
  • 28 Tsai CH, Shen YC, Chen HW, Liu KL, Chang JW, Chen PY, Lin CY, Yao HT, Li CC. Docosahexaenoic acid increases the expression of oxidative stress-induced growth inhibitor 1 through the PI3K/Akt/Nrf2 signaling pathway in breast cancer cells. Food Chem Toxicol 2017; 108: 276-288
    CrossrefPubMedGoogle Scholar
  • 29 Clerk A, Kemp TJ, Zoumpoulidou G, Sugden PH. Cardiac myocyte gene expression profiling during H2O2-induced apoptosis. Physiol Genomics 2007; 29: 118-127
    CrossrefPubMedGoogle Scholar
  • 30 Alexandre J, Batteux F, Nicco C, Chéreau C, Laurent A, Guillevin L, Weill B, Goldwasser F. Accumulation of hydrogen peroxide is an early and crucial step for paclitaxel-induced cancer cell death both in vitro and in vivo . Int J Cancer 2006; 119: 41-48
    CrossrefPubMedGoogle Scholar
  • 31 Xie S, Ogden A, Aneja R, Zhou J. Microtubule-binding proteins as promising biomarkers of paclitaxel sensitivity in cancer chemotherapy. Med Res Rev 2016; 36: 300-312
    CrossrefPubMedGoogle Scholar
  • 32 Wang TH, Chan YH, Chen CW, Kung WH, Lee YS, Wang ST, Chang TC, Wang HS. Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways. Oncogene 2006; 25: 4857-4866
    CrossrefPubMedGoogle Scholar
  • 33 Panis C, Lemos LGT, Victorino VJ, Herrera ACSA, Campos FC, Colado Simão AN, Pinge-Filho P, Cecchini AL, Cecchini R. Immunological effects of Taxol and Adryamicin in breast cancer patients. Cancer Immunol Immunother 2012; 61: 481-488
    CrossrefPubMedGoogle Scholar
  • 34 He W, Zhang MF, Ye J, Jiang TT, Fang X, Song Y. Cordycepin induces apoptosis by enhancing JNK and p38 kinase activity and increasing the protein expression of Bcl-2 pro-apoptotic molecules. J Zhejiang Univ Sci B 2010; 11: 654-660
    CrossrefPubMedGoogle Scholar
  • 35 Mantel CR, Gelfano VM, Kim YJ, McDaniel A, Lee Y, Boswell H, Broxmeyer HE. P21waf-1-Chk1 pathway monitors G1 phase microtubule integrity and is crucial for restriction transition. Cell Cycle 2002; 1: 327-336
    CrossrefPubMedGoogle Scholar
  • 36 Castedo M, Perfettini JL, Roumier T, Kroemer G. Cyclin-dependent kinase-1: Linking apoptosis to cell cycle and mitotic catastrophe. Cell Death Differ 2002; 9: 1287-1293
    CrossrefPubMedGoogle Scholar
  • 37 Zhang P, Kawakami H, Liu W, Zeng X, Strebhardt K, Tao K, Huang S, Sinicrope FA. Targeting CDK1 and MEK/ERK overcomes apoptotic resistance in BRAF-mutant human colorectal cancer. Mol Cancer Res 2018; 16: 378-389
    CrossrefPubMedGoogle Scholar
  • 38 Chen JG, Yang CP, Cammer M, Horwitz SB. Gene expression and mitotic exit induced by microtubule-stabilizing drugs. Cancer Res 2003; 63: 7891-7899
    PubMedGoogle Scholar
  • 39 Ahmed D, Eide PW, Eilertsen IA, Danielsen SA, Eknaes M, Hektoen M, Lind GE, Lothe RA. Epigenetic and genetic features of 24 colon cancer cell lines. Oncogenesis 2013; 2: e71
    CrossrefPubMedGoogle Scholar
  • 40 Sun H, Jiang L, Luo X, Jin W, He Q, An J, Lui K, Shi J, Rong R, Su W, Lucchesi C, Liu Y, Sheikh MS, Huang Y. Potential tumor-suppressive role of monoglyceride lipase in human colorectal cancer. Oncogene 2013; 32: 234-241
    CrossrefPubMedGoogle Scholar
  • 41 Hou S, Tiriac H, Sridharan BP, Scampavia L, Madoux F, Seldin J, Souza GR, Watson D, Tuveson D, Spicer TP. Advanced development of primary pancreatic organoid tumor models for high-throughput phenotypic drug screening. SLAS Discovery 2018; 23: 574-584
    CrossrefPubMedGoogle Scholar
  • 42 Becceneri AB, Fuzer AM, Popolin CP, Cazal CM, Domingues VC, Fernandes JB, Vieira PC, Cominetti MR. Acetylation of cedrelone increases its cytotoxic activity and reverts the malignant phenotype of breast cancer cells in 3D culture. Chem Biol Interact 2020; 316: 108920
    CrossrefPubMedGoogle Scholar
  • 43 Kohno T, Hai-Bang T, Zhu Q, Amen Y, Sakamoto S, Tanaka H, Morimoto S, Shimizu K. Tubulin polymerization-stimulating activity of Ganoderma triterpenoids . J Nat Med 2017; 71: 457-462
    CrossrefPubMedGoogle Scholar
  • 44 Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL, Vandesompele J, Wittwer CT. The MIQE guidelines: Minimum information for publication of quantitative real-time PCR experiments. Clin Chem 2009; 55: 611-622
    CrossrefPubMedGoogle Scholar