The Extract of Merremia mammosa Tubers Increases the Cytotoxicity of Doxorubicin and Induces Apoptosis in 4T1 Malignant Cancer Cells
Abstract
Doxorubicin has been incorporated in cancer therapy regimes for wide-range malignancies, but it causes many side effects. These adverse effects can be overcome by combining doxorubicin with other ingredients that possess anticancer potential but are safe on normal cells. The tubers of Merremia mammosa, locally known as “Bidara Upas” in Indonesia, have been proven to have anticancer potential with resin glycosides as the active compounds. This research aims to develop the extract of M. mammosa’s tubers (MTE) as a co-chemotherapy agent for doxorubicin. A malignant cancer cell line, 4T1, was used as the model. MTE was obtained by maceration in 96% ethanol. The thin layer chromatography confirmed that MTE contains glycoside compounds. Administration of MTE to 4T1 cells showed cytotoxic activity with an IC50 value of 61 μg/mL as evaluated by MTT assay. The combination of MTE and doxorubicin exhibited synergistic cytotoxic effects with a combination index of <0.7. Moreover, MTE at around IC50 was able to cause DNA fragmentation indicating apoptosis as observed by the agarose gel electrophoresis.These data support our hypothesis that MTE may serve as a potential co-chemotherapeutic agent for doxorubicin; however, the apoptosis-inducing potency of the combination requires further investigation.
Keywords: 4T1 cell, apoptosis, Bidara Upas, co-chemotherapy.
Full Text:
PDFReferences
A’yun, Q., 2016, Uji Sitotoksik Fraksi Etil Asetat Umbi Bidara Upas (Merremia mammosa (Lour.) Hall. F.) terhadap Sel Kanker Payudara T47D, Undergraduate Thesis, Universitas Setia Budi, Surakarta.
Cahyaningsih, R., Hidayat, S., and Hidayat, E., 2017, Perbanyakan Vegetatif Bidara Upas (Merremia mammosa (Lour.) Hallier f) Kebun Raya Bogor, Berita Biologi, 16(2), 167-174. CrossRef
Haagensen, E.J., Kyle, S., Beale, G.S., Maxwell, R.J., and Newell, D.R., 2012, The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition, British Journal of Cancer, 106(8), 1386–1394. CrossRef
Haryanti, S., Widiyastuti, Y., and Rahmawati, N., 2018, Cytotoxic and MMPs inhibitory activities of Sappan Wood (Caesalpinia sappan L.): various extracts on 4T1 breast cancer cell line, Health Science Journal of Indonesia, 9(1), 51–56. CrossRef
Ikawati, M., Jenie, R.I., Utomo, R.Y., Amalina, N.D., Ilmawati, G.P.N., Kawaichi, M., and Meiyanto, E., 2020, Genistein enhances cytotoxic and antimigratory activities of doxorubicin on 4T1 breast cancer cells through cell cycle arrest and ROS generation, Journal of Applied Pharmaceutical Science, 10(10), 95-104. CrossRef
Ikawati, M., Musyayyadah, H., Putri, Y.M., Zulfin, U.M., Wulandari, F., Putri, D.P.P., and Meiyanto, E., 2023, The synergistic effect of combination of Pentagamavunone-1 with diosmin, galangin, and piperine in WiDr colon cancer cells: in vitro and target protein prediction, Journal of Tropical Biodiversity and Biotechnology, 8(2), e80975. CrossRef
Kari, S., Subramanian, K., Altomonte, I. A., Murugesan, A., Yli-Harja, O., and Kandhavelu, M., 2022, Programmed cell death detection methods: a systematic review and a categorical comparison, Apoptosis: An International Journal on Programmed Cell Death, 27(7-8), 482–508. CrossRef
Kitagawa, I., Baek, N.I., Ohashi, K., Sakagami, M., Yoshikawa, M., and Shibuya, H., 1996, Indonesian Medicinal Plants. XV. Chemical structures of five new resin-glycosides, merremosides a, b, c, d, and e, from the tuber of Merremia mammosa (Convolvulaceae), Chemical & Pharmaceutical Bulletin (Tokyo), 44(9), 1680-1692. CrossRef
Kitagawa, I., Ohashi, K., Baek, N. I., Sakagami, M., Yoshikawa, M., and Shibuya, H., 1997, Indonesian Medicinal Plants. XIX. 1) Chemical structures of four additional resin-glycosides, mammosides A, B, H1, and H2, from the tuber of Merremia mammosa (Convolvulaceae), Chemical & Pharmaceutical Bulletin, 45(5), 786–794. CrossRef
Muna, L.N., and Jenie, R.I., 2018, Combination of curcuma (Curcuma xanthorriza Roxb) and awar-awar (Ficus septica Burm. F.) ethanolic extracts enhance doxorubicin to modulate cell cycle progression of T47D cells, Indonesian Journal of Cancer Chemoprevention, 9(1), 9-15. CrossRef
Nagano, T., Pospíšil, J., Chollet, G., Schulthoff, S., Hickmann, V., Moulin, E., et al., 2009, Total synthesis and biological evaluation of the cytotoxic resin glycosides ipomoeassin A–F and analogues, Chemistry–A European Journal, 15(38), 9697-9706. CrossRef
Nahar, M.N., Acharzo, A.K., Rahaman, M.S., Zabeen, I.A., Haque, S., and Islam, M.A., 2020, Phytochemical screening and antioxidant, analgesic, and anthelmintic effect of ethanolic extract of Merremia umbellate stems, Clinical Phytoscience, 6, 86. CrossRef
Newman, D.J., and Cragg, G.M., 2020, Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019, Journal of Natural Products, 83(3), 770–803. CrossRef
Nurrosyidah, I.H., Eka Saputri, E.O., Anwari, F., and Ningsih, A.W., 2022, Antibacterial activity of Indonesian Bidara Upas Tuber (Merremia mammosa L.) against pathogen bacteria, Gaceta Médica de Caracas, 130(Supl 5), S1153-S115. CrossRef
Olatunji, T.L., Adetunji, A.E., Olisah, C., Idris, O.A., Saliu, O.D., and Siebert, F., 2021, Research progression of the genus Merremia: a comprehensive review on the nutritional value, ethnomedicinal uses, phytochemistry, pharmacology, and toxicity, Plants (Basel, Switzerland), 10(10), 2070. CrossRef
Osborne, A., Adnani, Q.E.S., and Ahinkorah, B.O., 2025, Breast cancer incidence in Indonesia: a sex-disaggregated analysis using WHO health equity assessment toolkit data, BMC Cancer, 25(1), 986. CrossRef
Pereda-Miranda, R., Villatoro-Vera, R., Bah, M., and Lorence, A., 2009, Pore-forming activity of morning glory resin glycosides in model membranes, Revista Latinoamericana de Química, 37(2), 144-154.
Purwitasari, N., and Agil, M., 2022, Metabolite Profiling of extract and fractions of bidara upas (Merremia mammosa (Lour.) Hallier F.) tuber using UPLCQToF-MS/MS, Biomedical and Pharmacology Journal, 15(4), 2025–2041. CrossRef
Putri, D.D.P., Rivanti, E., Istiaji, R.P., and Meiyanto, E., 2021, Solanum nigrum ethanolic extract (SNE) increases cytotoxic activity of doxorubicin on MCF-7 Cell, Indonesian Journal of Cancer Chemoprevention, 12(2), 67-73. CrossRef
Putri, G.T.A., and Sakinah, E.N., 2020, Efek fraksi air ekstrak umbi bidara upas (Merremia mammosa (Lour.) Hailler f.) terhadap kepadatan kolagen pada luka tikus diabetes, Jurnal Tumbuhan Obat Indonesia, 13(1), 41-49. CrossRef
Rahmawati, Y., Setyawati, Y., Widodo, I., Ghozali, A., and Purnomosari, D., 2018, Molecular subtypes of Indonesian breast carcinomas - lack of association with patient age and tumor size, Asian Pacific Journal of Cancer Prevention, 19(1), 161-166. CrossRef
Ramadani, R.D., Utomo, R.Y., Hermawan, A., and Meiyanto, E., 2021, Pentagamaboronon-0- sorbitol induces apoptosis through elevation of reactive oxygen species in triple negative breast cancer cells, Indonesian Journal of Cancer Chemoprevention, 12(1), 46-56. CrossRef
Rathod, Z.R., Pooja, S., Sonali, M., Charin, P., Dhrumi, S., and Saraf, M.S., 2022, A review on qualitative and quantitative analysis of carbohydrates extracted from bacteria, Acta Scientific Pharmaceutical Sciences, 6(3), 20-28. CrossRef
Rivankar, S., 2014, An overview of doxorubicin formulations in cancer therapy, Journal of Cancer Research and Therapeutics, 10(4), 853– 858. CrossRef
Salimi, A., Zadeh, B.S.M., and Kazemi, M., 2019, Preparation and optimization of polymeric micelles for deferoxamine mesylate: In vitro and ex vivo studies, Research in Pharmaceutical Sciences, 14(4), 293-307. CrossRef
Tacar, O., Sriamornsak, P., and Dass, C.R., 2013, Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems, The Journal of Pharmacy and Pharmacology, 65(2), 157–170. CrossRef
Widiyastuti, Y., Sholikhah, I.Y.M., and Haryanti, S., 2019, Efek sitotoksik formula jamu daun sirsak, buah takokak, dan umbi bidara upas terhadap sel kanker payudara MCF-7, Jurnal Kefarmasian Indonesia, 9(2), 140-149. CrossRef
Zhu, D., Chen, C., Xia, Y., Kong, L.-Y., and Luo, J., 2019, A purified resin glycoside fraction from pharbitidis semen induces paraptosis by activating chloride intracellular channel-1 in human colon cancer cells, Integrative Cancer Therapies, 18, 1534735418822120. CrossRef
Zulfin, U.M., Rahman, A., Hanifa, M., Utomo, R.Y., Haryanti, S., and Meiyanto, E., 2021, Reactive oxygen species and senescence modulatory effects of rice bran extract on 4T1 and NIH- 3T3 cells co-treatment with doxorubicin, Asia Pacific Journal of Tropical Biomedicine, 11(4), 174-182. CrossRef
DOI: http://dx.doi.org/10.14499/indonesianjcanchemoprev16iss1pp57-66
Copyright (c) 2026 Indonesian Journal of Cancer Chemoprevention
Indexed by:
Indonesian Society for Cancer Chemoprevention
