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Senyawa Golongan Limonoid dari Tanaman Genus Chisocheton dan Aktivitas Antikankernya
Abstract
Indonesia merupakan negara yang kaya akan keanekaragaman hayati. Terdapat banyak tanaman yang mengandung senyawa metabolit sekunder yang memiliki aktivitas biologi sehingga berpotensi untuk digunakan sebagai obat, salah satunya adalah genus Chisocheton. Tanaman genus Chisocheton sudah banyak dilaporkan mengandung senyawa triterpenoid, seskuiterpenoid, limonoid, steroid, dan fenol. Limonoid merupakan turunan triterpenoid yang paling banyak ditemukan pada tanaman genus Chisocheton. Lebih dari tiga puluh senyawa golongan limonoid telah diuji aktivitas antikankernya terhadap beberapa jenis sel kanker manusia, seperti sel kanker payudara, mulut, paru-paru, leukimia, serviks, dan hati. Beberapa senyawa limonid tersebut diketahui memiliki aktivitas sitotoksik yang tinggi dengan kisaran nilai IC50 1,67 − 50,27 µg/mL. Review ini memaparkan beberapa senyawa limonoid yang diisolasi dari genus Chisocheton, aktivitas sitotoksiknya terhadap sel-sel kanker manusia, serta hubungan struktur dan aktifitas biologisnya (SAR = Structure Activity Relationship). Selain itu beberapa penelitian juga sudah melakukan penelitian lebih lanjut seperti pengujian induksi apoptosis dan penentuan tingkat ekspresi gen-gen yang berhubungan dengan apoptosis. Penelitian-penelitian yang dilakukan ini mengarah pada pencarian senyawa baru yang dapat digunakan sebagai lead compound untuk mendapatkan obat antikanker yang efektif.
Limonoid Compounds from Genus Chisocheton Plant and Its Anticancer Activity. Indonesia is a country with a large biodiversity. There are many plants contain secondary metabolite compounds with biological activity, such as Chisocheton genus. The Chisocheton is reported as plant with triterpenoids, sesquiterpenoids, limonoids, steroids and phenols content. Limonoids arethe derivative of triterpenoid which mostly found in Chisocheton genus. More than thirty limonoids have been studied for their anticancer activity against several types of human cancer cells, such as breast, mouth, lung, leukemia, cervical, and liver cancer cells. Some of these limonoids are known to have high cytotoxic activity with the IC50 values of 1.67 − 50.27 µg/mL. This review discuss many kind of limonoid compounds isolated from Chisocheton, their cytotoxic activity against human cancer cells, and their structural activity relationship (SAR) study. This review also discusses some research result for further studies of Chisocheton wether in the mechanism of apoptosis induction and also the determination genes level expression or proteins associated with the apoptosis. This review reveals the important of the study to find a new compounds for an effective anticancer drug.
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Abdel-Hameed, E.S.S., Bazaid, S.A., Shohayeb, M.M., El-Sayed, M.M., and El-Walkil, E.A., 2012. Phytochemical Studies and Evaluation of Antioxidant, Anticancer, and Antimicrobial Properties of Conocarpus erectus L. European Journal of Medicinal Plants 2(2), 93-112. doi: 10.9734/EJMP/2012/1040.
Amin, A.R.M., Kucuk, O., Khuri, F.R., and Shin, D.M., 2009. Perspectives for Cancer Prevention with Natural Compounds. Journal of Clinical Oncology 27(16), 2712-2725. doi: 10.1200/JCO.2008.20.6235.
Aslam, M.S., Naveed, S., Ahmed, A., Abbas, Z., Gull, I., and Athar, M.A., 2014. Side Effects of Chemotherapy in Cancer Patients and Evaluation of Patients Opinion about Starvation based Differential Chemotheraphy. Journal of Cancer Therapy 5(8), 817-822. doi: 10.4236/jct.2014.58089.
Aslanturk, O.S., 2018. In vitro Cytotoxicity and Cell Viability Assays: Principles, Advantages, and Disadvantages. Genotoxicity - A Predictable Risk to Our Actual World, 1-17. doi: 10.5772/intechopen.71923.
Atun, S., and Arianingrum, R., 2015. Anticancer Activity of Bioactive Compounds from Kaempferia rotunda Rhizome Against Human Breast Cancer. International Journal of Pharmacognosy and Phytochemical Research 7(2), 262-269.
Awang, K., Lim, C.S., Mohamad, K., Morita, H., Hirasawa, Y., Takeya, K., Thoison, E., and Hadi, A.H.A., 2007. Erythrocarpines A–E, New Cytotoxic Limonoids from Chisocheton erythrocarpus. Bioorganic and Medicinal Chemistry 15(17), 5997-6002. doi: 10.1016/j.bmc.2007.05.049.
Bordoloi, M., Saikia, B., Mathur, R.K., and Goswami, B.N., 1993. A Meliacin from Chisocheton panniculatus. Phytochemistry 34(2), 583–584. doi: 10.1016/0031-9422(93)80054-V.
Champagne, D.E., Koul, O., Isman, M.B., Scudder, G.G.E., and Neil Towers, G.H., 1992. Biological Activity of Limonoids from the Rutales. Phytochemistry 31(2), 377–394. doi: 10.1016/0031-9422(92)90003-9.
Chan, K.Y., Mohamad, K., Ooi, A.J.A., Imiyabir, Z., and Chung L.Y., 2012. Bioactivity-guided Fractionation of the Lipoxygenase and Cyclooxygenase Inhibiting Constituents from Chisocheton polyandrous Merr. Fitoterapia 83, 961-967. doi: 10.1016/j.fitote.2012.04.018.
Chatterjee, A., Nayak, L., Das, B., Patra, A., Dhara, K.P., Mukherjee, K., Banerji, J., and Shoolery, J.N., 1989. Chemistry of Phyto-constituents of Chisocheton Paniculatus Hiern (Meliaceae). Indian Journal Chemistry 28, 231. doi: 10.1016/j.phytol.2019.11.002.
Chen, J., Fan, X., Zhu, J., Song, L., Li, Z., Lin, F., Yu, R., Xu, H., and Zi, J., 2018. Limonoids from Seeds of Azadirachta indica A. Juss. and Their Cytotoxic Activity. Acta Pharmaceutica Sinica B 8(4), 639-644. doi: 10.1016/j.apsb.2017.12.009.
Chong, S.L., Hematpoor, A., Hazni, H., Azirun, M.S., Litaudon, M., Supratman, U., Murata, M., and Awang, K., 2019. Mosquito Larvacidal Limonoids from the Fruits of Chisocheton Erythrocarpus Hiern. Phytochemistry Letters 30, 69–73. doi: 10.1016/j.phytol.2018.12.013.
Dewick, M.P., 2009. Medicinal Natural Products: A Biosyntetic Approach. 3rd Edition. Jhon Willey and Sons, Nottingham.
Fang, X., Di, Y.T., and Hao, X.J., 2011. The Advances in the Limonoid Chemistry of the Meliaceae Family. Current Organic Chemistry 15, 1363–1391. doi: 10.2174/138527211795378254.
Fouad, Y. A., and Aanei, C., 2017. Revisiting the Hallmarks of Cancer. American Journal of Cancer Research 7(5), 1016-1036.
Guimarais, V.I., Guinon, E.G., Gabernet, G., Belinchon, M.G., Osuna, M.S., Casanelles, E., Comella, J.X., and Yuste, V.J., 2012. Apoptotic DNA Degradation into Oligonucleosomal Fragments, But Not Apoptotic Nuclear Morphology, Relies on a Cytosolic Pool of DFF40/CAD Endonuclease. The Journal of Biological Chemistry 287(10), 7766-7779. doi: 10.1074/jbc.M111.290718.
Gunning, P.J, Jeffs, L.B., Isman, M.B., Towers, G.H.N., and Ibrahim, K.S., 1994. Two Limonoids from Chisocheton microcarpus. Phytochemistry 36(5), 1245–1248. doi: 10.1016/S0031-9422(00)89645-4.
Govindachari, T.R., Malathi, R., Gopalakrishnan, G., Suresh, G., and Rajan, S.S., 1999. Isolation of a New Tetranortriterpenoid from the Uncrushed Green Leaves of Azadirachta indica. Phytochemistry 52(6), 1117–1119. doi: 10.1016/S0031-9422(99)00367-2.
Hanahan, D., and Weinberg, R.A., 2011. Hallmarks of Cancer: The Next Generation. Cell 144(5), 646-674. doi: 10.1016/j.cell.2011.02.013.
Heasley, B., 2011. Synthesis of Limonoid Natural Products. European Journal of Organic Chemistry 2011(1), 19-46. doi: 10.1002/ejoc.201001218.
Hidayat, A.T., Nurlelasari., Abdullah, F.F., Harneti, D., Maharani, R., Haikal, K., Supratman, U., and Azmi, M.N., 2018. A New Lignan Derivative, Lasiocarpone, from the Stembark of Chisocheton lasiocarpus (Meliaceae). Oriental Journal of Chemistry 34(4), 1956–1960. doi: 10.13005/ojc/3404032.
Hoai, N.T., Duc, H.V., Raal, A., and Morita, H., 2018. A New Limonoid from Chisocheton paniculatus Fruit Collected in Vietnam and Its NO Production Inhibitory Activity. Natural Product Communications 13(10), 1255-1257. doi: 10.1177/1934578X1801301005.
Inada, A., Somekawa, M., Murata, H., Nakanishi, T., Tokuda, H., Nishino, H., Iwashima, A., Darnaedi, D., and Murata, J., 1993. Phytochemical Studies on Meliaceous Plants. VIII. Structures and Inhibitory Effects on Epstein-barr Virus Activation of Triterpenoids from Leaves of Chisocheton macrophyllus King. Chemical and Pharmaceutical Bulletin 41(3), 617-619.
Jayaprakasha, G.K., Jadegoud, Y., Nagana Gowda, G.A., and Patil, B.S., 2010. Bioactive Compounds from Sour Orange Inhibit Colon Cancer Cell Proliferation and Induce Cell Cycle Arrest. Journal of Agricultural and Food Chemistry 58, 180–186. doi: 10.1021/jf9027816.
Jumiarni, W.O., and Komalasari, O., 2017. Eksplorasi Jenis dan Pemanfaatan Tumbuhan Obat pada Masyarakat Suku Muna di Permukiman Kota Wuna. Traditional Medicine Journal 22(1), 45-56.
Kalonio, D.E., Hendriani, R., and Barung, E.N., 2017. Aktivitas Antikanker Tanaman Genus Clerodendrum (Lamiaceae): Sebuah Kajian. Traditional Medicine Journal 22(3), 182-189. doi: 10.22146/mot.31554.
Katja, D.G., Farabi, K., Harneti, D., Mayanti, T., and Supratman, U., 2017. Cytotoxic Triterpenoid from the Stembark of Chisocheton celebicus (Meliaceae). Makara Journal of Science 21(1), 8-12. doi: 10.7454/mss.v21i1.7531.
Kipassa, N., 2008. Structural Studies of Tetranortriterpenoids from the Congolese species of Entandrophragma angolense And Efficient Short Step Synthesis of Corey’s Tamiflu Intermediate. Kagoshima University, Japan.
Kumar, P., Nagarajan, A., and Uchil, P.D., 2018. Analysis of Cell Viability by the MTT Assay. Cold Spring Harbor Protocols, 469-471. doi: 10.1101/pdb.prot095505.
Kurowska, E.M., Banh, C., Hasegawa, S., and Manners, G.D., 2000. Regulation of Apo Production in HepG2 Cells by Citrus Limonoids. Journal of Ameican Chemical Society 758, 175–184. doi: 10.1021/jf803712a.
Lee, C.S., Baek, J., and Han, S.Y., 2017. The Role of Kinase Modulators in Cellular Senescence for Use in Cancer Treatment. Molecules 22(9), 1-14. doi: 10.3390/molecules22091411.
Li, H., Peng, Y., and Zheng, J., 2016. Metabolic Activation and Toxicities of Furanoterpenoids. Advances in Molecular Toxicology 10, 55-97. doi: 10.1016/B978-0-12-804700-2.00002-7.
Liou, G.Y., and Storz, P., 2010. Reactive Oxygen Species in Cancer. National Institutes of Health Public Access 44(5), 1-31. doi: 10.3109/10715761003667554.
Maneerat, W., Laphookhieo, S., Koysomboon, S., and Chantrapromma, K., 2008. Antimalarial, Antimycobacterial and Cytotoxic Limonoids from Chisocheton siamensis. Phytomedicine 15(12), 1130–1134. doi: 10.1016/j.phymed.2008.05.004.
Mulholland, D.A., Osborne, R., Roberts, S.L., and Taylor, D.A.H., 1994. Limonoids and Triterpenoid Acids from the Bark of Entandrophragma delevoyi. Phytochemistry 37(5), 1417-1420. doi: 10.1016/S0031-9422(00)90423-0.
Mohamad, K., Hirasawa, Y., Lim, C.S., Awang, K., Hadi, A.H.A., Takeya, K., and Morita, H., 2008. Ceramicine A and Walsogyne A, Novel Limonoids from Two Species of Meliaceae. Tetrahedron Letters 49(27), 4276-4278. doi: 10.1016/j.tetlet.2008.04.145.
Mohamad, K., Hirasawa, Y., Litaudon, M., Awang, K., Hamid, A., Hadi, A., Takeya, K., Ekasari, W., Widyawaruyanti, A., Zaini, N.C., and Morita, H., 2009. Ceramicines B–D, New Antiplasmodial Limonoids from Chisocheton ceramicus. Bioorganic and Medicinal Chemistry 17(2), 727–730. doi: 10.1016/j.bmc.2008.11.048.
Nagoor, N.H., Muttiah, N.S.J., Lim, C.S., In, L.L.A., Mohammad, K., and Awang, K., 2011. Regulation of Apoptotic Effects by Erythrocarpine E, A Cytotoxic Limonoid from Chisocheton erythrocarpus in HSC-4 Human Oral Cancer Cells. PLOS one 6(8), 1-7. doi: 10.1371/journal.pone.0023661.
Neto, J.O., Agostinho, S.M.M., das G. F da Silva, M.F., Vieira, P.C., Fernandes, J.B., Pinheiro, A.L., and Vilela, E.F., 1995. Limonoids from Seeds of Toona ciliata and their Chemosystematic Significance. Phytochemistry 38(3), 397–401. doi: 10.1016/0031-9422(94)00568-E.
Niles, A.L., Moravec, R.A., and Riss, T.L., 2008. Update on in vitro Cytotoxicity Assays for Drug Development. Expert Opinion Drug Discovery 3(6), 655-669. doi: 10.1517/17460441.3.6.655.
Nugroho, B.W., Edrada, R.A., Wray, V., Witte, L., Bringmann, G., Gehling, M., and Proksch, P., 1999. An Insecticidal Rocaglamide Derivatives and Related Compounds from Aglaia odorata (Meliaceae). Phytochemistry 51(3), 367-376. doi: 10.1016/S0031-9422(98)00751-1.
Nurlelasari, Harneti, D., Mayanti, T., and Supratman, U., 2016. Senyawa Disobinin yang Bersifat Antimalaria dari Biji Tumbuhan Chisocheton macropyllus (Meliaceae). Al-Kimia. 4(2), 1-7. doi: 10.24252/al-kimia.v4i2.1675.
Nurlelasari., Katja, D.G., Harneti, D., Wardayo, M.M., Supratman, U., and Awang, K., 2017. Limonoids from the Seeds of Chisocheton macrophyllus. Chemistry of Natural Compounds 53(1), 83-87. doi: 10.1007/s10600-017-1916-4.
Nurlelasari., Muflihah., L.F., Wardoyo, M.M., Harneti, D., Puspa, H., and Awang, K., 2014. Senyawa 7-hidroksi-6-metoksi Kumarin yang Bersifat Sitotoksik dari Kulit Batang Chisocheton macrophyllus (Meliaceae). Bionatura-Jurnal Ilmu-ilmu Hayati dan Fisik 16(1), 59-61.
Patil, J., Kim, J., and Jayaprakasha, G., 2010. Berberine Induces Apoptosis in Breast Cancer Cells (MCF-7) through Mitochondrial-dependent Pathway. European Journal of Pharmacology 645, 70–78. doi: 10.1016/j.ejphar.2010.07.037.
Pettit, G.R., Barton, D.H.R., Herald, C.L., Polonsky, J., Schmidt, J.M., and Connolly, J.D., 1983. Evaluation of Limonoids Against the Murine P388 Lymphocytic Leukemia Cell Line. Journal of Natural Products 46, 379–390. doi: 10.1021/np50027a015.
Phongmaykin, J., Kumamoto, T., Ishikawa, T., Suttisri, R., and Saifah, E., 2008. A new Sesquiterpene and Other Terpenoid Constituents of Chisocheton penduliflorus. Archives of Pharmacal Research 31(1), 21-27. doi: 10.1007/s12272-008-1115-8.
Piow, W.C., 2012. Research of Ceramicines from Chisocheton ceramicus on Anti-Lipid Droplets Accumulation Activity. Xingji University Press., China.
Ponnusamy, S., Haldar, S., Mulani, F., Zinjarde, S., Thulasiram, H and RaviKumar, A., 2015. Gedunin and Azadiradione: Human Pancreatic Alpha-amylase Inhibiting Limonoids from Neem (Azadirachta indica) as Anti-diabetic Agents. PLOS ONE 10(10), 1-19. doi: 10.1371/journal.pone.0140113.
Poulose, S.M., Harris, E.D., and Patil, B.S., 2006. Antiproliferative Effects of Citrus Limonoids Against Human Neuroblastoma and Colonic Adenocarcinoma Cells. Journal of Nutrition and Cancer 56(1), 103–112. doi: 10.1207/s15327914nc5601_14.
Roy, A., and Saraf, S., 2006. Limonoids: Overview of Significant Bioactive Triterpenes Distributed in Plants Kingdom. Pharmaceutical Society of Japan 29(2), 191-201. doi: 10.1248/bpb.29.191.
Salim, Z., and Munadi, E., 2017. Info Komoditi Tanaman Obat. Badan Pengkajian dan Pengembangan Perdagangan., Jakarta.
Seca, A.M.L., and Pinto, D.C.G.A., 2018. Plant Secondary Metabolites as Anticancer Agents: Successes in Clinical Trials and Therapeutic Application. International Journal of Molecular Sciences 19(263), 1-22. doi: 10.3390/ijms19010263.
Senthil, S., and Nathan., 2013. Physiological and Biochemical Effect of Neem and other Meliaceae Plants Secondary Metabolites Against Lepidopteran Insects. Frontiers in Physiology 4(359), 1-17. doi: 10.3389/fphys.2013.00359.
Shilpi, J.A., Saha, S., Chong, S.L., Nahar, L., Sarker, S.D., and Awang, K., 2016. Advances in Chemistry and Bioactivity of the Genus Chisocheton Blume. Chem Biodiversity 13(5), 483-503. doi: 10.1016/j.phytol.2019.01.034.
Shin, S.A., Moon, S.Y., Kim, W.Y., Paek, S.M., Park, H.H., and Lee, C.S., 2018. Structure-based Classification and anti-cancer Effects of Plant Metabolites. International Journal of Molecular Sciences 19(9), 1-33. doi: 10.3390/ijms19092651.
Siddiqui, B.S., Afshan, F., Gulzar, T., and Hanif, M., 2004. Tetracyclic Triterpenoids from the Leaves of Azadirachta indica. Phytochemistry 65(16), 2363. doi: 10.1248/cpb.51.415.
Song, Y.H., Sun, H., Zhang, A.H., Yan, G.L., Han, Y., and Wang, X.J., 2014. Plant-derived Natural Products as Leads to Anti-cancer Drugs. Journal of Medicinal Plant and Herbal Therapy Research, 6-15.
Supratman, U., Salam, S., Naibaho, W., Fajar, M., Nurlelasari., Katja, D.G., Harneti, D., Maharani, R., Hidayat, A.T., Lesmana, R., Nafiah, M.A., and Shiono, Y., 2020. New Cytotoxic Limonoids from the Stem Bark of Chisocheton pentandrus (Blanco) merr. Phytochemistry Letters 35, 63-67. doi: 10.1016/j.phytol.2019.11.002.
Supriatno., Nurlelasari., Herlina, T., Harnetia, D., Maharania, R., Hidayat, A.T., Mayantia, T., Supratmana, U., Azmic, M.N., and Shiono, Y., 2018. A New Limonoid from Stem Bark of Chisocheton pentandrus (Meliaceae). Natural Product Research 32(21), 2610-2616. doi: 10.1080/14786419.2018.1428600.
Suresh, G., Narasimhan, N.S., and Palani, N., 1997. Structure of Nimonol from Fresh Whole Green Leaves of Azadirachta indica. Phytochemistry 45(4), 807–810. doi: 10.1016/S0031-9422(97)00038-1.
Tan, Q.G., and Luo, X.D., 2011. Meliaceous Limonoids: Chemistry and Biological Activities. Chemical Reviews 111(11), 7437-7522. doi: 10.1021/cr9004023.
Tasyriq, M., Najmuldeen, I.A., In, L.L.A., Mohamad, K., Awang, K., and Hasima, N., 2012. 7α-hydroxy-β-sitosterol from Chisocheton tomentosus Induces Apoptosis via Dysregulation of Cellular Bax/Bcl-2 Ratio and Cell Cycle Arrest by Downregulating ERK1/2 activation. Evidence-Based Complementary and Alternative Medicine 12(2), 1-12. doi: 10.1155/2012/765316.
Tundis, R., Loizzo, M.R., and Menichini, F., 2013. An Overview on Chemical Aspects and Potential Health Benefits of Limonoids and Their Derivatives. Critical Reviews in Food Science and Nutrition 54, 225-250. doi: 10.1080/10408398.2011.581400.
Venkata, K.C.N., Rathinavelu, A., and Bishayee, A., 2019. Limonoids: Structure–activity Relationship Studies and Anticancer Properties. Studies in Natural Products Chemistry 59, 375-399. doi: 10.1016/B978-0-444-64179-3.00011-6.
Wang, L.H., Wu, C.F., Rajasekaran, N., and Shin, Y.K., 2018. Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview. Cellular Physiology and Biochemistry 51, 2647-2693. doi: 10.1159/000495956.
Witantri, R.G., Ruspendi, E.C.A., and Saputro, D.S., 2015. Keanekaragaman Pohon Berpotensi Obat Antikanker di Kawasan Kampus Kentingan Universitas Sebelas Maret, Surakarta, Jawa Tengah. Conference: Seminar Nasional Masyarakat Biodiversitas Indonesia 1(3), pp. 477-483.
Wong, C.P., Kaneda, T., Hadi, A.H.A., and Morita, H., 2014. Ceramicine B, A Limonoid with Anti-lipid Droplets Accumulation Activity from Chisocheton ceramicus. Journal of Natural Medicines 68(1), 22-30. doi: 10.1007/s11418-013-0755-2.
Wong, C.P., Shimada, M., Nagakura, Y., Nugroho, A.E., Hirasawa, Y., Kaneda, T., Awang, K., Hadi, A.H.A., Mohamad, K., Shiro, M., and Morita, H., 2011. Ceramicines E—I, New Limonoids from Chisocheton ceramicus. Chemical and Pharmaceutical Bulletin 59(3), 407-411.
Wong, C.P., Shimada, M., Nugroho, A.E., Hirasawa, Y., Kaneda, T., Hadi, A.H.A., Osamu, S., and Morita, H., 2012. Ceramicines J–L, New Limonoids from Chisocheton ceramicus. Journal of Natural Medicines 66(3), 566–570. doi: 10.1007/s11418-011-0616-9.
Yadav, R., Pednekar, A., Avalaskar, A., Rathi, M.R.M, and Rewachandani, Y., 2015. A Comprehensive Review on Meliaceae Family. World Journal of Pharmaceutical Sciences 3(8), 1573-1577.
Yang, M.H., Wang, J.G., Luo, J.G., Wang, X.B., and Kong, L.Y., 2011. Chisopanins A-K, 11 New Protolimonoids from Chisocheton paniculatus and their Anti-inflammatory Activities. Bioorganic and Medical Chemistry 19(4), 1409-1417. doi: 10.1016/j.bmc.2011.01.007.
Zhang, Y., and Xu, H., 2017. Recent Progress in the Chemistry and Biology of Limonoids. Royal Society of Chemistry Advances 7(56), 35191-35220. doi: 10.1039/C7RA04715K.
