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Isovincathicine from Catharanthus roseus induces apoptosis in A549 cells

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Abstract

A dimeric indole alkaloid, isovincathicine consisting of an aspidosperma type and modified iboga with C-7–C-20 connection type skeletons was first isolated from Catharanthus roseus, and the structure including stereochemistry was elucidated on the basis of spectroscopic data as well as DP4 statistical analysis. Isovincathicine inhibited cell proliferation in A549 cells. We investigated the detailed mode of action of isovincathicine-induced inhibitory effects on cell proliferation in A549 cells. Flow cytometric analysis showed that isovincathicine-treated cells accumulated in the G2 phase after 24 h, and the percentage of cells showing cell death increased after 48 h. Western blotting also showed increased expression of BimEL, an apoptosis-related protein, and decreased expression of Mcl-1 and Bcl-xL. Isovincathicine was suggested to induce apoptosis in A549 cells by a mechanism is similar to that of vinblastine.

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References

  1. Dey A, Mukherjee A, Chaudhury M (2017) Alkaloids from Apocynaceae: origin, Pharmacotherapeutic properties, and structure-activity studies. Stud Nat Prod Chem 52:373–488

    Article  CAS  Google Scholar 

  2. Mohammed AE, Abdul-Hameed ZH, Alotaibi MO, Bawakid NO, Sobahi TR, Abdel-Lateff A, Alarif WM (2021) Chemical diversity and bioactivities of monoterpene indole alkaloids (MIAs) from six apocynaceae genera. Molecules 26:488. https://doi.org/10.3390/molecules26020488

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Hirasawa Y, Hattori R, Ohtani M, Uchiyama N, Hakamatsuka T, Morita H (2023) Cryptadine C, a new C27N3-type Lycopodium alkaloid from Lycopodium cryptomerinum. J Nat Med 77:610–613

    Article  PubMed  CAS  Google Scholar 

  4. Nugroho AE, Wong CP, Hirasawa Y, Kaneda T, Tougan T, Horii T, Hadi AHA, Morita H (2023) Ceramicines Q-T from Chisocheton ceramicus. J Nat Med 77:596–603

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Ogasawara A, Noguchi R, Shigi T, Nugroho AE, Hirasawa Y, Kaneda T, Tougan T, Horii T, Hadi AHA, Morita H (2022) Caloforines A-G, coumarins from the bark of Calophyllum scriblitifolium. J Nat Med 76:645–653

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Nugroho AE, Tange M, Kusakabe S, Hirasawa Y, Shirota O, Michiyo M, Mizukami H, Tougan T, Horii T, Morita H (2022) Chukranoids A-I, isopimarane diterpenoids from Chukrasia velutina. J Nat Med 76:756–764

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Hirasawa Y, Tanaka T, Hirasawa S, Wong DP, Uchiyama N, Kaneda T, Goda Y, Morita H (2022) Cliniatines A-C, new Amaryllidaceae alkaloids from Clivia miniata, inhibiting Acetylcholinesterase. J Nat Med 76:171–177

    Article  PubMed  CAS  Google Scholar 

  8. Hirasawa Y, Agawa-kakimoto M, Zaima K, Uchiyama N, Goda Y, Morita H (2021) Complanadine F, a novel dimeric alkaloid from Lycopodium complanatum. J Nat Med 75:403–407

    Article  PubMed  CAS  Google Scholar 

  9. Nugroho AE, Hirasawa Y, Kaneda T, Shirota O, Matsuno M, Mizukami H, Morita H (2021) Triterpenoids from Walsura trichostemon. J Nat Med 75:415–422

    Article  PubMed  CAS  Google Scholar 

  10. Kaneda T, Matsumoto M, Sotozono Y, Fukami S, Nugroho AE, Hirasawa Y, Hamid AHA, Morita H (2019) Cycloartane triterpenoid (23R, 24E)-23-acetoxymangiferonic acid inhibited proliferation and migration in B16–F10 melanoma via MITF downregulation caused by inhibition of both β-catenin and c-Raf–MEK1–ERK signaling axis. J Nat Med 73:47–58

    Article  PubMed  CAS  Google Scholar 

  11. Amelia P, Nugroho AE, Hirasawa Y, Kaneda T, Tougan T, Horii T, Morita H (2021) Two new bisindole alkaloids from Tabernaemontana macrocarpa Jack. J Nat Med 75:633–642

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Amelia P, Nugroho AE, Hirasawa Y, Kaneda T, Tougan T, Horii T, Morita H (2019) Two new sarpagine-type indole alkaloids and antimalarial activity of 16-demethoxycarbonylvoacamine from Tabernaemontana macrocarpa Jack. J Nat Med 73:820–825

    Article  PubMed  CAS  Google Scholar 

  13. Hirasawa Y, Dai X, Deguchi J, Hatano S, Sasaki T, Ohtsuka R, Nugroho AE, Kaneda T, Morita H (2019) New vasorelaxant indole alkaloids, taberniacins A and B, from Tabernaemontana divaricata. J Nat Med 73:627–632

    Article  PubMed  CAS  Google Scholar 

  14. Nugroho AE, Zhang W, Hirasawa Y, Tang Y, Wong CP, Kaneda T, Hadi AHA, Morita H (2018) Bisleuconothines B-D, modified eburnane–aspidosperma bisindole alkaloids from Leuconotis griffithii. J Nat Prod 81:2600–2604

    Article  PubMed  CAS  Google Scholar 

  15. Nugroho AE, Hirasawa Y, Wong CP, Kaneda T, Hadi AHA, Shirota O, Ekasari W, Widyawaruyanti A, Morita H (2012) Antiplasmodial indole alkaloids from Leuconotis griffithii. J Nat Med 66:350–353

    Article  PubMed  CAS  Google Scholar 

  16. Motegi M, Nugroho AE, Hirasawa Y, Arai T, Hadi AHA, Morita H (2012) Leucomidines A-C, novel alkaloids from Leuconotis griffithii. Tetrahedron Lett 53:1227–1230

    Article  CAS  Google Scholar 

  17. Nugroho AE, Hirasawa Y, Hosoya T, Awang K, Hadi AHA, Morita H (2010) Bisleucocurine a, a novel bisindole alkaloid from Leuconotis griffithii. Tetrahedron Lett 51:2589–2592

    Article  CAS  Google Scholar 

  18. Hirasawa Y, Shoji T, Arai T, Nugroho AE, Deguchi J, Hosoya T, Uchiyama N, Goda Y, Awang K, Hadi AHA, Shiro M, Morita H (2010) Bisleuconothine A, an eburnane-aspidosperma bisindole alkaloid from Leuconotis griffithii. Bioorg Med Chem Lett 20:2021–2024

    Article  PubMed  CAS  Google Scholar 

  19. Tang Y, Nugroho AE, Hirasawa Y, Tougan T, Horii T, Hadi AHA, Morita H (2019) Leucophyllinines A and B, bisindole alkaloids from Leuconotis eugeniifolia. J Nat Med 73:533–540

    Article  PubMed  CAS  Google Scholar 

  20. Nugroho AE, Ono Y, Jin E, Hirasawa Y, Kaneda T, Rahman A, Kusumawati I, Tougan T, Horii T, Zaini NC, Morita H (2021) Bisindole alkaloids from Voacanga grandifolia Leaves. J Nat Med 75:408–414

    Article  PubMed  CAS  Google Scholar 

  21. Morita H, Haseo A, Nugroho AE, Hirasawa Y, Kaneda T, Shirota O, Rahman A, Kusumawati I, Cholies Zaini N (2015) A new indole alkaloid from Voacanga grandifolia. Heterocycles 90:601–606

    Article  Google Scholar 

  22. Hirasawa Y, Yasuda R, Minami W, Hirata M, Nugroho AE, Tougan T, Uchiyama N, Hakamatsuka T, Horii T, Morita H (2021) Divaricamine a, a new anti-malarial trimeric monoterpenoid indole alkaloid from Tabernaemontana divaricata. Tetrahedron Lett 83:153423

    Article  CAS  Google Scholar 

  23. Mayer S, Keglevich P, Keglevich A, Hazai L (2021) New anticancer vinca alkaloids in the last decade. Curr Org Chem 25:1224–1234

    Article  CAS  Google Scholar 

  24. Svoboda, G. H.; Barnes, A. J. Jr. (1964) Alkaloids of Vinca rosea. XXIV. Vinaspine, vincathicine, rovidine, deacetylvincaleukoblastine, and vinaphamine. J Pharm Sci 53: 1227-1231

  25. Tafur SS, Occolowitz JL, Elzey TK, Paschal JW, Dorman DE (1976) Alkaloids of Vinca rosea L. (Catharanthus roseus G. Don). XXXVII. Struct of Vincathicine J Org Chem 41:1001–1005

    Article  CAS  Google Scholar 

  26. Langlois H, Andriamialisoa RZ, Neuss N (1980) Bis-indolic alkaloids of Catharanthus ovalis. Helv Chim Acta 63:793–803

    Article  CAS  Google Scholar 

  27. Abraham DJ, Farnsworth NR (1969) Structure elucidation and chemistry of Catharanthus alkaloids III: structure of leurosine, an active anticancer alkaloid. J Pharm Sci 58:694–698

    Article  PubMed  CAS  Google Scholar 

  28. Smith SG, Goodman JM (2010) Assigning stereochemistry to single Diastereoisomers by GIAO NMR calculation: the DP4 probability. J Am Chem Soc 132:12946–12959

    Article  PubMed  CAS  Google Scholar 

  29. Grimblat N, Gavín JH, Daranas A, Sarotti AM (2019) Combining the power of J coupling and DP4 analysis on Stereochemical assignments: the J-DP4 methods. Org Lett 21:4003–4007

    Article  PubMed  CAS  Google Scholar 

  30. Cairns E, Hashmi MA, Singh AJ, Eakins G, Lein M, Keyzers R (2015) Structure of Echivulgarine, a Pyrrolizidine alkaloid isolated from the pollen of Echium vulgare. J Agric Food Chem 63:7421–7427

    Article  PubMed  CAS  Google Scholar 

  31. Dong JG, Bornmann W, Nakanishi K, Berova N (1995) Structural studies of vinblastine alkaloid by exciton coupled circular dichroism. Phytochemistry 40:1821–1824

    Article  PubMed  CAS  Google Scholar 

  32. Upreti M, Lyle CS, Skaug B, Du L, Chambers TC (2006) Vinblastine-induced apoptosis is mediated by discrete alterations in subcellular location, oligomeric structure, and activation status of specific Bcl-2 family members. J Biol Chem 281:15941–15950

    Article  PubMed  CAS  Google Scholar 

  33. Chen D, Zhou Q (2004) Caspase cleavage of BimEL triggers a positive feedback amplification of apoptotic signaling. Proc Natl Acad Sci USA 101:1235–1240

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Singh PK, Roukounakis A, Weber A, Das KK, Sohm B, Villunger A, Garcia-Saez AJ, Häcker G (2020) Dynein light chain binding determines complex formation and posttranslational stability of the Bcl-2 family members Bmf and Bim. Cell Death Differ 27:434–450

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was partly supported by JSPS KAKENHI (JP 19K07152 and JP 22K06671 to MH) and (22K06685 to YH), Japan.

Funding

This work was partly supported by JSPS KAKENHI (JP 19K07152 and JP 22K06671 to MH) and (22K06685 to YH), Japan.

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Author notes

  1. Mizuki Hiroki and Aishanjiang Abulikemu contributed equally to this work

Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo, 142-8501, Japan

    Mizuki Hiroki, Aishanjiang Abulikemu, Chihiro Totsuka, Yusuke Hirasawa, Toshio Kaneda & Hiroshi Morita

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  1. Mizuki Hiroki
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  2. Aishanjiang Abulikemu
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  3. Chihiro Totsuka
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  4. Yusuke Hirasawa
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  5. Toshio Kaneda
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  6. Hiroshi Morita
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Contributions

MH, AA, CT, YH, TK, and HM conceived and designed the experiments; MH, YH, TK, and HM wrote the paper.

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Correspondence to Yusuke Hirasawa or Hiroshi Morita.

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Hiroki, M., Abulikemu, A., Totsuka, C. et al. Isovincathicine from Catharanthus roseus induces apoptosis in A549 cells. J Nat Med 78, 216–225 (2024). https://doi.org/10.1007/s11418-023-01740-8

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