Dichloromethane Fraction of Vernonia amygdalina Delile Synergistically Enhances Cytotoxicity of Doxorubicin on 4T1 Triple Negative Breast Cancer Cells through Apoptosis Induction and Cell Cycle Modulation
Keywords:
Vernonia amygdalina Delille, TNBC, Co-treatment, cell cycle, apoptosis
Abstract
Doxorubicin (Dox) belongs to the chemotherapeutics agent that is commonly used to cure non-specific markers of cancers, including Triple Negative Breast Cancers (TNBC). Due to its toxicity to normal cells, the use of Dox is usually accompanied by another agent to increase the potency or to reduce the adverse effects. This study investigated the potential of Africa Leaf (Vernonia amygdalina Delile) extracts in combination treatment with Dox to increase the cytotoxicity in accordance with cell cycle modulation and apoptosis induction on TNBC cells. The MTT cell viability assay on 4T1 and MDA-MB-231 cells confirmed that only dichloromethane (DCM) fraction showed cytotoxic activities on both cells in a low grade. The DCM fraction increased the cytotoxic activity of Dox on 4T1 cells in a synergistic manner. The synergistic effect correlated with its activities in cell cycle modulation to accumulate the cells in sub-G1 phase and significantly induced apoptosis. In conclusion, the DCM fraction exhibits potential to be a co-chemotherapeutics agent for Dox to suppress TNBC cells growth through apoptosis induction.
References
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Yeap, S. K., Ho, W. Y., Beh, B. K., Liang, W. S., Ky, H., Yousr, A. H. N., & Alitheen, N. B. (2010). Vernonia amygdalina, an ethnoveterinary and ethnomedical used green vegetable with multiple bioactivities. Journal of medicinal plants research, 4(25), 2787-2812.
Al-Mahmood, S., Sapiezynski, J., Garbuzenko, O. B., & Minko, T. (2018). Metastatic and triple-negative breast cancer: challenges and treatment options. Drug delivery and translational research, 8, 1483-1507.
Asensio-López, M. C., Soler, F., Sánchez-Más, J., Pascual-Figal, D., Fernández-Belda, F., & Lax, A. (2016). Early oxidative damage induced by doxorubicin: source of production, protection by GKT137831 and effect on Ca2+ transporters in HL-1 cardiomyocytes. Archives of Biochemistry and Biophysics, 594, 26-36.
Caesar, L. K., & Cech, N. B. (2019). Synergy and antagonism in natural product extracts: when 1+ 1 does not equal 2. Natural product reports, 36(6), 869-888.
Harahap, U., Dalimunthe, A., Haro, G., Syahputra, R. A., Utomo, D. H., & Satria, D. (2021). In-silico ANALYSIS OF CARDIAC GLYCOSIDES FROM Vernonia amygdalina Delile. LEAVES AS CARDIOTONIC THROUGH INHIBITION OF Na+/K+ ATPase ION TRANSPORT. Rasayan Journal of Chemistry, 14(1).
Igile, G. O., Oleszek, W., Jurzysta, M., Burda, S., Fafunso, M., & Fasanmade, A. A. (1994). Flavonoids from Vernonia amygdalina and their antioxidant activities. Journal of Agricultural and Food Chemistry, 42(11), 2445-2448.
Ijeh, I. I., & Ejike, C. E. C. C. (2011). Current perspectives on the medicinal potentials of Vernonia amygdalina Del. Journal of medicinal plants research, 5(7), 1051-1061.
Luo, X., Jiang, Y., Fronczek, F. R., Lin, C., Izevbigie, E. B., & Lee, K. S. (2011). Isolation and structure determination of a sesquiterpene lactone (vernodalinol) from Vernonia amygdalina extracts. Pharmaceutical biology, 49(5), 464-470.
Kumar, P., & Aggarwal, R. (2016). An overview of triple-negative breast cancer. Archives of gynecology and obstetrics, 293, 247-269.
O'Reilly, D., Al Sendi, M., & Kelly, C. M. (2021). Overview of recent advances in metastatic triple negative breast cancer. World journal of clinical oncology, 12(3), 164.
Obidiro, O., Battogtokh, G., & Akala, E. O. (2023). Triple Negative Breast Cancer Treatment Options and Limitations: Future Outlook. Pharmaceutics, 15(7), 1796.
Ohigashi, H., Jisaka, M., Takagaki, T., Nozaki, H., Tada, T., Huffman, M. A., ... & Koshimizu, K. (1991). Bitter principle and a related steroid glucoside from Vernonia amygdalina, a possible medicinal plant for wild chimpanzees. Agricultural and Biological Chemistry, 55(4), 1201-1203.
Ponte, L. G. S., Pavan, I. C. B., Mancini, M. C. S., da Silva, L. G. S., Morelli, A. P., Severino, M. B., ... & Simabuco, F. M. (2021). The hallmarks of flavonoids in cancer. Molecules, 26(7), 2029.
Quasie, O., Zhang, Y. M., Zhang, H. J., Luo, J., & Kong, L. Y. (2016). Four new steroid saponins with highly oxidized side chains from the leaves of Vernonia amygdalina. Phytochemistry Letters, 15, 16-20.
Salsabila, I. A., Nugraheni, N., Ahlina, F. N., Haryanti, S., & Meiyanto, E. (2021). Synergistic cotreatment potential of soursop (Annona muricata L.) leaves extract with Doxorubicin on 4T1 cells with antisenescence and anti-reactive-oxygen-species properties. Iranian Journal of Pharmaceutical Research: IJPR, 20(2), 57.
Sarmoko, S., Novitasari, D., Toriyama, M., Fareza, M. S., Choironi, N. A., Itoh, H., & Meiyanto, E. (2023). Different Modes of Mechanism of Gamma-Mangostin and Alpha-Mangostin to Inhibit Cell Migration of Triple-Negative Breast Cancer Cells Concerning CXCR4 Downregulation and ROS Generation. Iranian Journal of Pharmaceutical Research, (In Press).
Sinisi, A., Millán, E., Abay, S. M., Habluetzel, A., Appendino, G., Muñoz, E., & Taglialatela-Scafati, O. (2015). Poly-electrophilic sesquiterpene lactones from Vernonia amygdalina: new members and differences in their mechanism of thiol trapping and in bioactivity. Journal of Natural Products, 78(7), 1618-1623.
Syahputra, R. A., Harahap, U., Harahap, Y., Gani, A. P., Dalimunthe, A., Ahmed, A., & Zainalabidin, S. (2023). Vernonia amygdalina Ethanol Extract Protects against Doxorubicin-Induced Cardiotoxicity via TGFβ, Cytochrome c, and Apoptosis. Molecules, 28(11), 4305.
Wong, F. C., Woo, C. C., Hsu, A., & Tan, B. K. H. (2013). 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, 8(10), e78021.
Yeap, S. K., Ho, W. Y., Beh, B. K., Liang, W. S., Ky, H., Yousr, A. H. N., & Alitheen, N. B. (2010). Vernonia amygdalina, an ethnoveterinary and ethnomedical used green vegetable with multiple bioactivities. Journal of medicinal plants research, 4(25), 2787-2812.
Published
2024-05-15
How to Cite
Rahmawati, D. R., Nugraheni, N., Hapsari, N. P., Hanifa, M., Prasetyaningrum, P. W., Kastian, R. F., Satria, D., Hasibuan, P. A. Z., Meiyanto, E., & Septisetyani, E. P. (2024). Dichloromethane Fraction of Vernonia amygdalina Delile Synergistically Enhances Cytotoxicity of Doxorubicin on 4T1 Triple Negative Breast Cancer Cells through Apoptosis Induction and Cell Cycle Modulation. Indonesian Journal of Pharmacy. https://doi.org/10.22146/ijp.11209
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Section
Research Article
