Africa leaf (Vernonia amygdalina Delille.) DCM extract synergistically supports growth suppression effect of doxorubicin on MCF7 and MCF7/HER2 with different effects on cell cycle progression and apoptosis evidence

Novia Permata Hapsari Desty Restia Rahmawati Nadzifa Nugraheni Mila Hanifa Denny Satria Poppy Anjelisa Zaitun Hasibuan Edy Meiyanto   

Open Access   

Published:  May 08, 2024

DOI: 10.7324/JAPS.2024.180163
Abstract

Africa leaf (Vernonia amygdalina Delille) has low cytotoxic activities against several cancer cells. We evaluated its combination treatment with doxorubicin against luminal breast cancer cells against MCF-7 and MCF-7/HER2 cells. The dried leaves were extracted to collect Hexane, Butanol, Dichloromethane (DCM), and ethyl acetate (EA) extracts and were then tested for their cytotoxic activities on MCF7 and MCF7/HER2 cells using MTT assay. The most potential extracts were then examined for cytotoxicity in combination treatment with doxorubicin followed by cell cycle and apoptosis analysis with flow cytometry. All the extracts showed low and no cytotoxic activities against both MCF7 and MCF7/HER2 cells. The DCM extract exhibited a weak cytotoxic activity on both cancer cells with the IC50 values of 220 μg/ml. However, DCM and EA extracts gave synergistic cytotoxic effects with Dox on both cells with strong synergism characteristics. Both extracts induced cell cycle accumulation on the S-phase for DCM and the G1 phase for EA. Both extracts also caused apoptosis with Dox but in different ways in modulating apoptosis. In conclusion, DCM and EA extract of V. amygdalina provide potential synergistic anticancer properties with Dox for luminal breast cancer through cell cycle modulation and apoptosis induction.


Keyword:     Vernonia amygdalina Delille MCF-7 MCF-7/HER2 cell cycle apoptosis


Citation:

Hapsari NP, Rahmawati DR, Nugraheni N, Hanifa M, Satria D, Hasibuan PAZ, Meiyanto E. Africa leaf (Vernonia amygdalina Delille.) DCM extract synergistically supports growth suppression effect of doxorubicin on MCF7 and MCF7/HER2 with different effects on cell cycle progression and apoptosis evidence. J Appl Pharm Sci. 2024. Online First. http://doi.org/10.7324/JAPS.2024.180163

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Reference

1. Novitasari D, Jenie RI, Kato JY, Meiyanto E. Chemoprevention curcumin analog 1.1 promotes metaphase arrest and enhances intracellular reactive oxygen species levels on TNBC MDA-MB-231 and HER2-positive HCC1954 cells. Res Pharm Sci. 2023 Jul 1;18(4):358-70. https://doi.org/10.4103/1735-5362.378083

2. Hermawan A, Putri H. Identification of potential gene associated with berberine in overcoming tamoxifen resistance by functional network analysis. J Appl Pharm Sci. 2020 Jun 30;10(7):009-18.

3. Zhang Z, Park JW, Ahn IS, Diamante G, Sivakumar N, Arneson D, et al. Estrogen receptor alpha in the brain mediates tamoxifen-induced changes in physiology in mice. Elife. 2021 Mar 1;10:e63333. https://doi.org/10.7554/eLife.63333

4. Hermawan A, Ikawati M, Khumaira A, Putri H, Jenie RI, Angraini SM, et al. Bioinformatics and in vitro studies reveal the importance of p53, PPARG and notch signaling pathway in inhibition of breast cancer stem cells by hesperetin. Adv Pharm Bull. 2021 Feb;11(2):351. https://doi.org/10.34172/apb.2021.033

5. Handayani S, Susidarti RA, Utomo RY, Meiyanto E, Jenie RI. Synergistic cytotoxic and antimigratory effect of brazilein and doxorubicin on HER2-overexpressing cells. Asian Pac J Cancer Prev. 2022 Aug;23(8):2623. https://doi.org/10.31557/APJCP.2022.23.8.2623

6. Nurhayati IP, Khumaira A, Ilmawati GP, Meiyanto E, Hermawan A. Cytotoxic and antimetastatic activity of hesperetin and doxorubicin combination toward Her2 expressing breast cancer cells. Asian Pac J Cancer Prev. 2020 May;21(5):1259. https://doi.org/10.31557/APJCP.2020.21.5.1259

7. Wulandari F, Novitasari D, Kirihata M, Kato JY, Meiyanto E. New curcumin analog, CCA-1.1, synergistically improves the antiproliferative effect of doxorubicin against T47D breast cancer cells. Indones J Pharm. 2020;31:244-56. https://doi.org/10.22146/ijp.681

8. Ikawati M, Jenie RI, Utomo RY, Amalina ND, Ilmawati GP, Kawaichi M, et al. Genistein enhances cytotoxic and antimigratory activities of doxorubicin on 4T1 breast cancer cells through cell cycle arrest and ROS generation. J Appl Pharm Sci. 2020 Oct 5;10(10):095-104.

9. Rawat PS, Jaiswal A, Khurana A, Bhatti JS, Navik U. Doxorubicin-induced cardiotoxicity: an update on the molecular mechanism and novel therapeutic strategies for effective management. Biomed Pharmacother. 2021 Jul 1;139:111708. https://doi.org/10.1016/j.biopha.2021.111708

10. Salsabila IA, Nugraheni N, Ahlina FN, Haryanti S, Meiyanto E. Synergistic cotreatment potential of soursop (Annona muricata L.) leaves extract with Doxorubicin on 4T1 cells with antisenescence and anti-reactive-oxygen-species properties. Iran J Pharm Res. 2021;20(2):57.

11. Amalina ND, Salsabila IA, Zulfin UM, Jenie RI, Meiyanto E. In vitro synergistic effect of hesperidin and doxorubicin downregulates epithelial-mesenchymal transition in highly metastatic breast cancer cells. J Egypt Natl Cancer Inst. 2023 Dec;35(1):6. https://doi.org/10.1186/s43046-023-00166-3

12. Hermawan A, Putri H. Targets and molecular mechanisms of a citrus flavonoid, hesperidin, against luminal breast cancer cells: an integrative bioinformatics analysis. Asian Pac J Trop Biomed. 2019 Dec 1;9(12):531-8. https://doi.org/10.4103/2221-1691.271727

13. Ahlina FN, Nugraheni N, Salsabila IA, Haryanti S, Da'i M, Meiyanto E. Revealing the reversal effect of galangal (Alpinia galanga L.) extract against oxidative stress in metastatic breast cancer cells and normal fibroblast cells intended as a co-chemotherapeutic and anti-ageing agent. Asian Pac J Cancer Prev. 2020 Jan 1;21(1):107-17. https://doi.org/10.31557/APJCP.2020.21.1.107

14. Alif I, Utomo RY, Ahlina FN, Nugraheni N, Hermansyah D, Putra A, et al. Immunopotentiation of galangal (Alpinia galanga L.) when combined with T-cells against metastatic triple-negative breast cancer, MDA-MB 231. J Appl Pharm Sci. 2021 Jul 18;11(11):053-61. https://doi.org/10.7324/JAPS.2021.1101107

15. Zulfin UM, Rahman A, Hanifa M, Utomo RY, Haryanti S, Meiyanto E. Reactive oxygen species and senescence modulatory effects of rice bran extract on 4T1 and NIH-3T3 cells co-treatment with doxorubicin. Asian Pac J Trop Biomed. 2021 Apr 1;11(4):174-82. https://doi.org/10.4103/2221-1691.310204

16. Com?a ?, Cimpean AM, Raica M. The story of MCF-7 breast cancer cell line: 40 years of experience in research. Anticancer Res. 2015 Jun 1;35(6):3147-54.

17. Zhao S, Ohara S, Kanno Y, Midorikawa Y, Nakayama M, Makimura M, et al. HER2 overexpression-mediated inflammatory signaling enhances mammosphere formation through up-regulation of aryl hydrocarbon receptor transcription. Cancer Lett. 2013 Mar 1;330(1):41-8. https://doi.org/10.1016/j.canlet.2012.11.021

18. Nowak J, Kiss AK, Wambebe C, Katuura E, Ku?ma ?. Phytochemical analysis of polyphenols in leaf extract from Vernonia amygdalina Delile plant growing in Uganda. Appl Sci. 2022 Jan 17;12(2):912. https://doi.org/10.3390/app12020912

19. Ondua M, Njoya EM, Abdalla MA, McGaw LJ. Anti-inflammatory and antioxidant properties of leaf extracts of eleven South African medicinal plants used traditionally to treat inflammation. J Ethnopharmacol. 2019 Apr 24;234:27-35. https://doi.org/10.1016/j.jep.2018.12.030

20. Okello D, Chung Y, Kim H, Lee J, Rahmat E, Komakech R, et al. Antioxidant activity, polyphenolic content, and FT-NIR analysis of different Aspilia africana medicinal plant tissues. Evid Based Complement Altern Med. 2021 Sep 15;2021:e9917810. https://doi.org/10.1155/2021/9917810

21. Hasibuan PA, Harahap U, Sitorus P, Satria D. The anticancer activities of Vernonia amygdalina Delile. Leaves on 4T1 breast cancer cells through phosphoinositide 3-kinase (PI3K) pathway. Heliyon. 2020 Jul 1;6(7):e04449. https://doi.org/10.1016/j.heliyon.2020.e04449

22. Wong FC, Woo CC, Hsu A, Tan BK. The anti-cancer activities of Vernonia amygdalina extract in human breast cancer cell lines are mediated through caspase-dependent and p53-independent pathways. PLoS One. 2013 Oct 24;8(10):e78021. https://doi.org/10.1371/journal.pone.0078021

23. Owor RO, Bedane KG, Openda YI, Zühlke S, Derese S, Ong'amo G, et al. Synergistic anti-inflammatory activities of a new flavone and other flavonoids from Tephrosia hildebrandtii Vatke. Nat Prod Res. 2021 Nov 18;35(22):4486-93. https://doi.org/10.1080/14786419.2020.1736065

24. Kim CH, Kim JE, Song YJ. Antiviral activities of quercetin and isoquercitrin against human herpesviruses. Molecules. 2020 May 20;25(10):2379. https://doi.org/10.3390/molecules25102379

25. Sugiura Y, Katsuzaki H, Imai K, Amano H. The anti-allergic and anti-inflammatory effects of phlorotannins from the edible brown algae, Ecklonia sp. and Eisenia sp. Nat Prod Commun. 2021 Nov;16(12):1934578X211060924. https://doi.org/10.1177/1934578X211060924

26. Harahap U, Dalimunthe A, Haro G, Syahputra RA, Utomo DH, Satria D. In-silico analysis of cardiac glycosides from vernonia amygdalina delile. leaves as cardiotonic through inhibition of NA+/K+ ATPase ion transport. Rasayan J Chem. 2021 Jan 1;14(1):161-5.

27. Syahputra RA, Harahap U, Harahap Y, Gani AP, Dalimunthe A, Ahmed A, et al. Vernonia amygdalina ethanol extract protects against doxorubicin-induced cardiotoxicity via TGFβ, cytochrome c, and apoptosis. Molecules. 2023 May 24;28(11):4305. https://doi.org/10.3390/molecules28114305

28. Luo X, Jiang Y, Fronczek FR, Lin C, Izevbigie EB, Lee KS. Isolation and structure determination of a sesquiterpene lactone (vernodalinol) from Vernonia amygdalina extracts. Pharm Biol. 2011 May 1;49(5):464-70. https://doi.org/10.3109/13880209.2010.523429

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