Anticancer activity of novel soursop leaves active compound (sf-1603) through apoptotic induction in liver cancer


  • Maya Tejasari Bandung Islamic University
  • Herri Sastramihardja Padjadjaran University
  • Siti Aminah Abdurachman Padjadjaran University
  • Dwi Prasetyo Padjadjaran University



Apoptosis, liver cancer, soursop (Annona muricata) leaves, targetted therapy


There are no effective standard treatments for unresectable stage of liver cancer have been established. These insights lead the pursuit of targeted therapeutic strategies for reactivating apoptosis to eradicate cancer cells. It was hypothesized that active compound in the soursop leaves will be able to induce apoptosis. Objective of the study is to explore the role of novel soursop leaves active compound (SF-1603) in apoptosis induction to find a new agent for liver cancer therapy.  This study was use HepG2 cell line culture seeded in DMEM / F12. There were control group and 3 intervention group given SF-1603 with different concentration.  Apoptosis detection was done using Terminal deoxynucleotidyl Transferase-mediated dUTP Nick End Labeling (TUNEL) method. Statistical analyses were conducted using linear regression. The result showed the cells undergoing apoptosis in the control group less than treatment groups.  There was a strong positive correlation (r=0.847) between the rate of apoptosis and a concentration of SF-1603, reflected the  apoptotic effect with a dose-dependent manner. The study conclude, the novel  soursop  leaves  active compound SF-1603 had the strong ability to induce apoptosis on liver cancer cell line culture, so it can be used as a candidate for new agent for liver cancer therapy.

Author Biographies

Maya Tejasari, Bandung Islamic University

Faculty of Medicine

Herri Sastramihardja, Padjadjaran University

Faculty of Medicine

Siti Aminah Abdurachman, Padjadjaran University

Faculty of Medicine

Dwi Prasetyo, Padjadjaran University

Pediatric Department, Faculty of Medicine


Accomando, S., Pellitteri, V., Corsello, G. 2010. Natural polyphenols as anti inflammatory agents. Fornt Biosci, 2, 318-331.

Adewole S. O., Ojewole, J., A. 2008. Protective effects of annona muricata linn. (annonaceae) leaf aqueous extract on serum lipid profiles and oxidative stress in hepatocytes of streptozotocin-treated diabetic rats. African journal of traditional, complementary and alternative medicines, 6, 1, 30-41.

Adina, A., Handoko, F., Setyarini, I., Septisetyani, Riyanto, S., Meyranto, E. 2009. Ekstrak etanolik kulit jeruk nipis (citrus aurantifolia (cristm.) swingle) meningkatkan sensitivitas sel mcf-7 terhadap doxorubicin. Kongres ilmiah ISFI ke-16, Yogyakarta, Indonesia, 55-62.

Agouni, A., Lagrus-Lak-Hal, A., Tesse, A., Mulder, P., et al. 2009. Red wine polyphenols prevent metabolic and cardiovascular alterations associated with obesity in zucker fatty rats (Fa/Fa). PLos One, 4, e5557. (rev)

Albert B, Johnson A.Lewis J, Morgan D, Raf M, 2015. Molecular biology of the cell. Edisi ke-4. New York (6 ed.). New York: Garland Science Taylor and Francis Group Company.

Baharvand, A., Ali, R., Yusof, A. M., Ibrahim, A. N., Chandren, S., Nur, H. 2014. Preparation of anatase hollow TiO2 spheres and their photocatalytic activity in the photodegradation of chlorpyrifos. Journal of the Chinese Chemical Society, 61, 11, 1211-1216.

Bassiouny, A., Bassiouni, N., Nosseir, M., Zoheiry, M., El-Ahwany, G., et al. 2008. Circulating and hepatic fas expression in hcv-induced chronic live disease and hepatocellular carcinoma. Medscape Journal of Medicine, 10, 6, 130.

Batra, P., Sharma, A. K. 2013. Anti-cancer potensial of flavonoids: Recent trends and future perspective. 3Biotech, 3(6), 439-459.

Benitez, D., Pozo-Guisado, E., Alvarez-Barrientos, A., Fernandez-Salguero, P., Castellón, E. 2007. Mechanisms involved in resveratrol-induced apoptosis and cell cycle arrest in prostate cancer-derived cell lines. Journal of Andrology, 28, 282-293.

Bravo, L. 1998. Polyphenols: Chemistry, dietary source, metabolism and nutritional significance. Nutrition Reviews, 56, 317-333.

Bruix, J., Sherman, M. 2005. Management of hepatocellular carcinoma. Journal of Hepatology, 42, 5, 1208-1236.

Cagle, P., Allen, T. 2009. Apoptosis. In Basic concept of molecular pathology (pp. 32-38): Springer Dordrecht Heidelberg.

Cardoso, A., Moucari, R., Mendes, C., Ripault, M., Giully, N., Castelnau, C. 2010. Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: Incidence and survival in hepatitis c patients with advanced fibrosis. . Jjhep, 52, 652-657.

Cha, C., DeMatteo, R. 2005. Molecular mechanisms in hepatocellular carcinoma development. Practise & Research Clinical Gastroenterology, 19, 1, 25-37.

Chang, Y., Xu, Y. 2000. Expression of BCL-2 inhibited fas-mediated apoptosis in human hepatocellular carcinoma BEL-7404 cells., Cell Research, 10 (3), 233-242.

Cherniack, E. 2011. Polyphenols: Planning the seeds of treatment for the metabolic syndrome. Nutrition, 27, 617-623.

Chiu, H., Chih, T., Hsian, Y., Tseng, C., Wu, M., Wu, Y. 2003. Bullatacin, a potent antitumor annonaceous acetogenins, induces apoptosis through a reduction of intracellular camp and cgmp levels in human hepatoma 2.2.15 cells. Biochemical Pharmacology, 65, 3, 319-327.

Coloma, A., Guadan-o, A., Ine’sa, C., Martinez-Diazb, R., Cortesc, D. 2002. Selective action of acetogenin mitochondrial complex i inhibitors. Z Naturforsch, 57C, 1028-1034.

D’Archivio, M., Santangelo, C., Scazzocchio, B., Varì, R., Filesi, C. 2008. Modulatory effects of polyphenols on apoptosis induction: Relevance for cancer prevention. International Journal of Molecular Sciences, 9, 213-228.

Dai, J., Mumper, R. 2010. Plant phenolics: Extraction, analysis and their antioxidant and anticancer properties. Molecules, 15, 7313-7352.

Dashwood, R. 2007. Frontiers in polyphenols and cancer prevention. Journal of Nutrition, 37, 267S-269S.

Fajarningsih, N., Nursid, M., Wikanta, T., Marraskuranto, E. 2008. Bioaktivitas ekstrak turbinaria decurrens sebagai antitumor serta efeknya terhadap proliferasi limfosit. Jurnal Pascapanen dan Bioteknologi Kelautan dan Perikanan, 3, 1.

Fraga, C. G., Oteiza, P. I. 2011. Dietary flavonoids : Role of (-)-epicatechin and related procyanidins in cell signaling. Free Radical Biology & Medicine, 51, 813-823.

Ghassan, K., Abou-alfa, M. Huitzil-Melendez FD, Saltz L. 2007. . Current and novel therapeutics for hepatocellular carcinoma (American society of Clinical Oncology). Gastrointest Cancer Research 2(2).

Grassi, D., Desideri, G., Groce, G., Tiberti, S., Anggio, A., et al, 2009. Flavonoids, vascular function and cardiovascular protection. Current Pharmaceutical Design, 15, 1072-1084.

Guo, W., Kong, E., Meydani, M. 2009. Dietary polyphenols, inflammation and cancer. Nutrition and Cancer, 61, 807-810.

Gutierez-Merino, C., Lopez-sanchez, C., Lagoa, R., Samhan-Arias, A., Bueno, C., al, e. 2011. Neuroprotective actions of flavonoids. Current Medicinal Chemistry, 18, 1195-1212.

Hanahan, D., Weinberg, R. 2000. The hallmarks of cancer. Cell, 100, 57-70.

He, H., Wu, X., Yu, B., Liu, K., Zhou, G., Qian, G., et al. 2010. The effect of desacetyluvaricin on the expression of TLR4 and P53 protein in Hepg 2.2.15. Journal of Hepatitis, 11, 5, 364-367.

Ho, H., Pok, S., Streit, S., Ruhe, J., Hart, S., Lim, K., et al. 2009. Fibroblast growth factor receptor 4 regulates proliferation, anti-apoptosis and alpha-fetoprotein secretion during hepatocellular carcinoma progression and represents a potential target for therapeutic intervention. Journal of Hepatology, 50, 118-127.

Huynh, H., Ngo, V., Koong, H., Poon, D., S, S. C., Toh, H., et al. 2010. Azd6244 enhances the anti-tumor activity of sorafenib in ectopic and orthotopis models of hcc. Journal of Hepatology, 52, 79-87.

Irene, M., Ghobrial, M., Thomas, E., Witzig, M., Alex, A., Adjei, M. 2005. Targeting apoptosis pathways in cancer therapy. CA: A Cancer Journal for Clinicians, 55, 178-194.

Kampa, M., Nifli, A., Notas, G., Castanas, E. 2007. Polyphenols and cancer cell growth. Reviews of Physiology, Biochemistry and Pharmacology, 159, 79-113.

Korkina, L., Luca, C. D., Kostyuk, V., Pastore, S. 2009. Plant polyphenols and tumors: From mechanism to therapies, prevention and protection againts toxicity of anti-cancer treatments. Current Medicinal Chemistry, 16, 3943-3965.

Kumar, V., Cotran, R., Robbin, S. 2003. Pathologic basic of disease (7 ed.). Philadelphia: Saunders-Elsevier.

Lee, S., Shin, M., Lee, H., Bae, J., Lee, K., H, K., et al. 2001. Expression of fas and fas-related molecules in human hepatocellular carcinoma. Human Pathology, 32, 3, 250-256.

Lencioni, R., Crocetti, L., Petruzzi, P., Vignali, C., Bozzi, W., C, C. P., et al. 2008. Doxorubicin-eluting bead-enhanced radiofrequency ablation of hepatocellular carcinoma:A pilot clinical study. Journal of Hepatology, 49, 217-222.

Liu, Q., Chen, J., Liu, L., Zhang, J., Wang, D., Ma, L., et al. 2011. The x protein of hepatitis b virus inhibits apoptosis in hepatoma cell through enchancing the methionine adenosyltransferase 2a gene expression and reducing s-adenosylmethionine production. The Journal of Biological Chemistry, 286, 19, 17168-17180.

Lu, G., Xiao, H., You, H., Lin, Y., Jin, H. 2008. Synergistic inhibition of lung tumorigenesis by a combination of green tea polyphenols and atorvastatin. Clinical Cancer Research, 14, 4981-4988.

Lu, X., Lee, M., Tran, T., Block, T. 2005. High level expression of apoptosis inhibitor in hepatoma cell line expressing hepatitis B virus. International Journal of Medical Sciences, 2, 1, 30-35.

Manach, C., Scallbert, A., Morand, C., Remesy, S., Jimenez, L. 2004. Polyphenols: Food sources and bioavailability. American Journal of Clinical Nutrition, 79, 727-747.

Martin, K. R. 2006. Targeting apoptosis with dietary bioactive agents. Experimental Biology and Medicine, 231, 117-29.

Tejasari, Sastramihardja, HS., Abdurachman SA, Prasetyo D. 2016. SF-1603; soursop leaves new active compound. A candidate for hepatocellular carcinoma therapy on fas as a new molecular target. Paper presented at the The 3rd Asia Future Conference, Kitakyushu-Japan (29 sept-3 oct), Proceeding Digital ISSN 2432-0528.

Tejasari, Shahib N., Sastramihardja HS, Iwan D. 2014. The role of soy in preventing apoptosis in liver injury. International Journal of Research in Pharmaceutical and Nano Science, 3, 5, 373-379.

Milne, J., Lambet, P., Schenk, S., Carney, D., Smith, J., al, e. 2007. Small molecule activators of sirt1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 712-716.

Muharni, Supriyatna, Husein, H., Bahti, Dachriyanus. 2009. Phenolic compound from the stem bark of manggis hutan (garcinia bancana miq.) and their antioxidant acctivity. Indonesian Journal of Chemistry., 9 (2), 321 - 327.

Park, S., Lee, Y., Han, S., Kwon, S., Kwon, O., Kim, S., et al. 2006. Systemic chemotherapy with doxorubicin, cisplatin and capecitabine for metastatic hepatocellular carcinoma. BMC Cancer, 6, 3, 10.1186/1471-2407-1186-1183.

Queen, B., Tollefsbol, T. 2010. Polyphenols and aging. Current Aging Science, 3, 34-42.

Quideau, S., Deffieux, D., Douat-Casassus, C., Pouysegu, L. 2011. Plant pholyphenols: Chemical properties, biological activities and synthesis. Angew Chem Int Ed Engl. 50(3). 582-621.

Robotin, M., Kansil, M., Howard, K., George, J., Tipper, S., Dores, G., et al. 2009. Antiviral therapy for hepatitis b-related cancer prevention is more cost-effective than cancer screening. Journal of Hepatitis, 50, 990-998.

Rodriguez, M. L., Estrela, J. M., Ortega, A. L. 2013. Natural polyphenols and apoptosis induction in cancer therapy. Journal of Carcinogenesis and Mutagenesis, S6, 004.

Saha, A., Kuzuhara, T., Echigo, N., Suganuma, M., Fujiki, H. 2010. New role of (−)-epicatechin in enhancing the induction of growth inhibition and apoptosis in human lung cancer cells by curcumin. Cancer prevention Research, 3, 953-962.

Sherman, M., Burak, K., Maraun, J., Metrakos, P., Myers, R., Guindi, M., et al. 2011. Multidiciplinary canadian concensus recommendations for the management and treatment of hepatocellular carcinoma. Current Oncology, 18, 5, 228-240.

Sies, H. 2010. Pholyphenols and health: Update and perspectives. Archives of Biochemistry and Biophysics, 501, 2-5.

Song, Y., Zhang, A., Yan, G., Han, Y., Wang, X. 2014. Pant-derived natural products as leads to anti-cancer drugs. Journal of Medicinal Plant and Herbal Therapy Research, 6, 15.

Spengler, U. 2012. Diagnosis, prognosis & therapy in hepatology. In Hepatology a Clinical Textbook (pp. 302-312): Flying Publisher, USA.

Steeg, P. 2006. Tumor metastasis: Mechanistic insights and clinical challenges. Nature Medicine, 12, 895-904.

Tejasari, M., Shahib, N., Iwan, D., Sastramihardja, H. S. 2013. Peran kedelai (glycine max l.) dalam pencegahan apoptosis pada cedera jaringan hati. Global Medical & Health Communication, 2, 1, 15-20.

Thorgeirsson, S., Grisham, J. 2002. Molecular pathogenesis of human hepatocellular carcinoma. Nature Genetics, 31.

Wirth, T., Kuhnel, F., Fleischmann-Mundt, B., Woller, N., Djojosubroto, M., Rudolph, K., et al. 2005. Telomerase-dependent virotherapy overcomes resistance of hepatocellular carcinomas against chemotherapy and tumor necrosis factor-related apoptosis-inducing ligand by elimination of MCL-1 Cancer Resarch Journal 65, 7393-7402.

Wong, S. R. 2011. Apoptosis in cancer: From pathogenesis to treatment. Journal of Experimental & Clinical Cancer Research, 30(87), 30, 87.

Wu, F., Zeng, L., Gu, Z., Zhao, G., Zhang, Y., Schwedler, J., et al. 1995. New bioactive monotetrahydrofuran annonaceous acetogenins, annonamuricin C and muricatocin C, from leaves of annona muricata. Journal of Natural Products, 58, 6, 909-915.

Yildiz, L., Baris, S., Aydin, O., Kefeli, M., Kandemir, B. 2008. BCL-2 positivity in B and C hepatitis and hepatocellular carcinoma. Hepatogastroeneterology, 55, 88, 2207-2210.

Yuan, Z., Chen, L., Fan, L., Tang, M., Yang, G. 2006. Liposomal quercetin efficiently suppresses growth of solid tumors in murine models. Clinical Cancer Reseacrh Journal, 12, 3193-3199.

Yuniarti, L., Sastramihardja, H., Purbaningsih, W., Tejasari, M., Respati, T., Hestu, E., et al. 2014. Soursop effect in cervical cancer apoptosys mechanism. Global Medical & Health Communication, 2, 1, 6-14.

Zhao, B. 2009. Natural antioxidant protect neuron in alzheimers disesase and parkonsons disease. Neurochemical Research, 34, 630-638.