Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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1,3,5-Tricaffeoylquinic Acid from Ipomoea batatas Vines Induced Ovarian Cancer Cell Apoptosis and Inhibited Endothelial Tube Formation

  • Dahae Lee (College of Korean Medicine, Gachon University) ;
  • Jaekyoung Kim (Natural Products Research Institute, College of Pharmacy, Seoul National University) ;
  • Soyoon Baek (R&D Complex, Kolmar Korea) ;
  • Jin Woo Lee (College of Pharmacy, Duksung Women's University) ;
  • Changyeol Lee (Herbal Medicine Resources Center, Korea Institute of Oriental Medicine) ;
  • Ki Sung Kang (College of Korean Medicine, Gachon University) ;
  • Sang Hee Shim (Natural Products Research Institute, College of Pharmacy, Seoul National University)
  • Received : 2024.12.11
  • Accepted : 2025.01.28
  • Published : 2025.05.01
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Abstract

Ovarian cancer usually metastasizes from the ovary to adjacent organs through direct invasion with blood vessels formed by endothelial cells. Targeting apoptosis of ovarian cancer and angiogenesis is promising for anticancer therapy. Leaves of Ipomoea sp. have reportedly shown promise in treating ovarian cancer. Here, we investigated the apoptosis-inducing and anti-angiogenic effects of compounds isolated from Ipomoea batatas vines (IBV). Phytochemical examination of IBV led to the isolation and verification of eight compounds (1-8): chlorogenic acid (1), 3,4-dicaffeoylquinic acid (2), 3,5-dicaffeoylquinic acid (3), 4,5-dicaffeoylquinic acid (4), 1,3,5-tricaffeoylquinic acid (5), N-trans-feruloyltyramine (6), scopoletin (7), and esculetin (8). Of these, 1,3,5-tricaffeoylquinic acid (5) showed the highest cytotoxicity in A2780 human ovarian cancer cells, inducing apoptotic death in more than 37% cells and decreasing viability to less than 25% at 100 μM. Compound 5 increased the levels of cleaved caspase-8, Bax, cleaved PARP, and caspase-3/9, and decreased the levels of cleaved Bcl-2. Further, 5 inhibited tubule formation in HUVECs. VEGFR2, ERK, PI3K, Akt, and mTOR protein expression was also suppressed by 5. Then, a simple, rapid, and reliable LC-MS/MS method was developed to determine the contents of the isolated compounds from IBV. Overall, 5 has potential for treating ovarian cancer as it induces apoptosis in ovarian cancer cells and inhibits tube formation.

Keywords

Acknowledgement

This research was supported by the National Research Foundation of Korea (NRF-2021R1A2C1004958 and NRF-2022R1A4A3022401).

References

  1. Al-Alem, L. F., Baker, A. T., Pandya, U. M., Eisenhauer, E. L. and Rueda, B. R. (2019) Understanding and targeting apoptotic pathways in ovarian cancer. Cancers (Basel) 11, 1631. https://doi.org/10.3390/cancers11111631
  2. Aouad, S. M., Cohen, L. Y., Sharif-Askari, E., Haddad, E. K., Alam, A. and Sekaly, R.-P. (2004) Caspase-3 is a component of Fas death-inducing signaling complex in lipid rafts and its activity is required for complete caspase-8 activation during Fas-mediated cell death. J. Immunol. 172, 2316-2323. https://doi.org/10.4049/jimmunol.172.4.2316
  3. Beneke, R., Geisen, C., Zevnik, B., Bauch, T., Muller, W. U., Kupper, J. H. and Moroy, T. (2000) DNA excision repair and DNA damageinduced apoptosis are linked to poly(ADP-ribosyl)ation but have different requirements for p53. Mol. Cell. Biol. 20, 6695-6703. https://doi.org/10.1128/MCB.20.18.6695-6703.2000
  4. Bhatt Mehul, K., Dholwani Kishor, K. and Saluja Ajay, K. (2011) Isolation and structure elucidation of scopoletin from Ipomoea reniformis (Convolvulaceae). J. Appl. Pharm. Sci. 1, 138-144.
  5. Cui, C. B., Jeong, S. K., Lee, Y. S., Lee, S. O., Kang, I. J. and Lim, S. S. (2009) Inhibitory activity of caffeoylquinic acids from the aerial parts of Artemisia princes on rat lens aldose reductase and on the formation of advanced glycation end products. J. Korean Soc. Appl. Biol. Chem. 52, 655-662. https://doi.org/10.3839/jksabc.2009.109
  6. DeCicco-Skinner, K. L., Henry, G. H., Cataisson, C., Tabib, T., Gwilliam, J. C., Watson, N. J., Bullwinkle, E. M., Falkenburg, L., O'Neill, R. C. and Morin, A. (2014) Endothelial cell ube formation assay for the in vitro study of angiogenesis. J. Vis. Exp. 91, e51312.
  7. Doubeni, C. A., Doubeni, A. R. and Myers, A. E. (2016) Diagnosis and management of ovarian cancer. Am. Fam. Physician 93, 937-944.
  8. Gentile, M. T., Pastorino, O., Bifulco M. and Colucci-D'Amato, L. (2019) HUVEC tube-formation assay to evaluate the impact of natural products on angiogenesis. J. Vis. Exp. 148, e58591.
  9. Hu, W. and Kavanagh, J. J. (2003) Anticancer therapy targeting the apoptotic pathway. Lancet Oncol. 4, 721-729. https://doi.org/10.1016/S1470-2045(03)01277-4
  10. Islam, M. S., Yoshimoto, M., Yahara, S., Okuno, S., Ishiguro, K. and Yamakawa, O. (2002) Identification and characterization of foliar polyphenolic composition in sweetpotato (Ipomoea batatas L.) genotypes. J. Agric. Food Chem. 50, 3718-3722. https://doi.org/10.1021/jf020120l
  11. Jiang, T., Ye, S., Liao, W., Wu, M., He, J., Mateus, N. and Oliveira, H. (2022) The botanical profile, phytochemistry, biological activities and protected-delivery systems for purple sweet potato (Ipomoea batatas (L.) Lam.): an up-to-date review. Food Res. Int. 161, 111811. https://doi.org/10.1016/j.foodres.2022.111811
  12. Jin, F., Xie, T., Huang, X. and Zhao, X. (2018) Berberine inhibits angiogenesis in glioblastoma xenografts by targeting the VEGFR2/ERK pathway. Pharm. Biol. 56, 665-671. https://doi.org/10.1080/13880209.2018.1548627
  13. Kanada, R. M., Simionato, J. I., Arruda, R. F. D., Santin, S. M. D. O., Souza, M. C. D. and Silva, C. C. D. (2012) N-trans-feruloyltyramine and flavonol glycosides from the leaves of Solanum sordidum. Rev. Bras. Farmacogn. 22, 502-506. https://doi.org/10.1590/S0102-695X2012005000029
  14. Karar, J. and Maity, A. (2011) PI3K/AKT/mTOR pathway in angiogenesis. Front. Mol. Neurosci. 4, 51.
  15. Kim, N. M., Kim, J., Chung, H. Y. and Choi, J. S. (2000) Isolation of luteolin 7-O-rutinoside and esculetin with potential antioxidant activity from the aerial parts of Artemisia montana. Arch. Pharm. Res. 23, 237-239. https://doi.org/10.1007/BF02976451
  16. Kim, S. J., Nah, S. Y., Park, I. H., Shin, M. S. and Kang, K. S. (2023) Gintonin isolated from ginseng inhibits the epithelial-mesenchymal transition induced by TGF-beta in A549 lung cancer cells. Plants 12, 2013. https://doi.org/10.3390/plants12102013
  17. Kutkowska, J., Strzadala, L. and Rapak, A. (2021) Hypoxia increases the apoptotic response to betulinic acid and betulin in human nonsmall cell lung cancer cells. Chem. Biol. Interact. 333, 109320. https://doi.org/10.1016/j.cbi.2020.109320
  18. Lamanuzzi, A., Saltarella, I., Desantis, V., Frassanito, M. A., Leone, P., Racanelli, V., Nico, B., Ribatti, D., Ditonno, P., Prete, M., Solimando, A. G., Dammacco, F., Vacca, A. and Ria, R. (2018) Inhibition of mTOR complex 2 restrains tumor angiogenesis in multiple myeloma. Oncotarget 9, 20563-20577. https://doi.org/10.18632/oncotarget.25003
  19. Lee, D., Yu, J. S., Ha, J. W., Lee, S. R., Lee, B. S., Kim, J. C., Kim, J. K., Kang, K. S. and Kim, K. H. (2022) Antitumor potential of withanolide glycosides from Ashwagandha (Withaniasomnifera) on apoptosis of human hepatocellular carcinoma cells and tube formation in human umbilical vein endothelial cells. Antioxidants 11, 1761. https://doi.org/10.3390/antiox11091761
  20. Maiuri, M. C., Zalckvar, E., Kimchi, A. and Kroemer, G. (2007) Selfeating and self-killing: crosstalk between autophagy and apoptosis. Nat. Rev. Mol. Cell Biol. 8, 741-752.
  21. Markman, M., Webster, K., Zanotti, K., Peterson, G., Kulp, B. and Belinson, J. (2004) Survival following the documentation of platinum and taxane resistance in ovarian cancer: a single institution experience involving multiple phase 2 clinical trials. Gynecol. Oncol. 93, 699-701. https://doi.org/10.1016/j.ygyno.2004.03.023
  22. Mohanraj, R. and Sivasankar, S. (2014) Sweet potato (Ipomoea batatas [L.] Lam)-a valuable medicinal food: a review. J. Med. Food 17, 733-741. https://doi.org/10.1089/jmf.2013.2818
  23. Monk, B. J., Herzog, T. J. and Tewari, K. S. (2016) Evolution of chemosensitivity and resistance assays as predictors of clinical outcomes in epithelial ovarian cancer patients. Curr. Pharm. Des. 22, 4717-4728. https://doi.org/10.2174/1381612822666160505114326
  24. Naora, H. and Montell, D. J. (2005) Ovarian cancer metastasis: integrating insights from disparate model organisms. Nat. Rev. Cancer 5, 355-366. https://doi.org/10.1038/nrc1611
  25. Noumi, E. (2010) Ethno medicines used for treatment of prostatic disease in Foumban, Cameroon. Afr. J. Pharmacy Pharmacol. 4, 793-805.
  26. Pezzuto, J. M. (1997) Plant-derived anticancer agents. Biochem. Pharmacol. 53, 121133.
  27. Pistollato, F., Giampieri, F. and Battino, M. (2015) The use of plant-derived bioactive compounds to target cancer stem cells and modulate tumor microenvironment. Food Chem. Toxicol. 75, 58-70. https://doi.org/10.1016/j.fct.2014.11.004
  28. Pradeep, C., Sunila, E. and Kuttan, G. (2005) Expression of vascular endothelial growth factor (VEGF) and VEGF receptors in tumor angiogenesis and malignancies. Integr. Cancer Ther. 4, 315-321. https://doi.org/10.1177/1534735405282557
  29. Reed, J. C. (2002) Apoptosis-based therapies. Nat. Rev. Drug Discov. 1, 111-121. https://doi.org/10.1038/nrd726
  30. Roy, A., Datta, S., Bhatia, K. S., Jha, P. and Prasad, R. (2021) Role of plant derived bioactive compounds against cancer. S. African J. Bot. 149, 1017-1028.
  31. Scappaticci, F. A. (2002) Mechanisms and future directions for angiogenesis-based cancer therapies. J. Clin. Oncol. 20, 3906-3927. https://doi.org/10.1200/JCO.2002.01.033
  32. Scorrano, L. and Korsmeyer, S. J. (2003) Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochem. Biophys. Res. Commun. 304, 437-444. https://doi.org/10.1016/S0006-291X(03)00615-6
  33. Tsuji-Tamura, K., Sato, M., Fujita, M. and Tamura, M. (2020) The role of PI3K/Akt/mTOR signaling in dose-dependent biphasic effects of glycine on vascular development. Biochem. Biophys Res. Commun. 529, 596-602. https://doi.org/10.1016/j.bbrc.2020.06.085
  34. Wu, F., Song, H., Zhang, Y., Zhang, Y., Mu, Q., Jiang, M., Wang, F., Zhang, W., Li, L. and Li, H. (2015) Irisin induces angiogenesis in human umbilical vein endothelial cells in vitro and in zebrafish embryos in vivo via activation of the ERK signaling pathway. PLoS One 10, e0134662. https://doi.org/10.1371/journal.pone.0134662
  35. Zanetta, G., Chiari, S., Rota, S., Bratina, G., Maneo, A., Torri, V. and Mangioni, C. (1997) Conservative surgery for stage I ovarian carcinoma in women of childbearing age, BJOG-Int. J. Obstet. GY. 104, 1030-1035. https://doi.org/10.1111/j.1471-0528.1997.tb12062.x
  36. Zhang, C., Liu, D., Wu, L., Zhang, J., Li, X. and Wu, W. (2019) Chemical characterization and antioxidant properties of ethanolic extract and its fractions from sweet potato (Ipomoea batatas L.) leaves. Foods 9, 15. https://doi.org/10.3390/foods9010015
  37. Zhao, J. G., Yan, Q. Q., Xue, R. Y., Zhang, J. and Zhang, Y. Q. (2014) Isolation and identification of colourless caffeoyl compounds in purple sweet potato by HPLC-DAD–ESI/MS and their antioxidant activities. Food Chem. 161, 22-26. https://doi.org/10.1016/j.foodchem.2014.03.079