PENGARUH PEMBERIAN EKSTRAK DAUN SIRSAK (Annona muricata Linn) TERHADAP GEN ANTI APOPTOSIS BCL-2 CONTINOUS CELL T47D PADA KANKER PAYUDARA
Abstrak
Pendahuluan: Kanker payudara menduduki peringkat pertama kasus terbanyak keganasan di Indonesia. Studi fitokimia asetogenin sebagai substansi utama dari sirsak berpotensi sebagai agen sitotoksik dan memicu apoptosis sel kanker payudara.
Metode: Penelitian ini merupakan jenis true eksperimental menggunakan studi in-vitro dengan menggunakan continous cell T47D yang diinkubasi selama 72 jam pada dua kelompok studi, kelompok perlakuan diberi larutan ekstrak etanol daun sirsak dengan konsentrasi sesuai IC-50 94,26 µg/ml. Hasil penelitian ini dilihat dari nilai cycle quantification RT-PCR yang akan dilakukan analisis uji normalitas Saphiro Wilk, analisis kemaknaan Mann-Whitney Test, dan penentuan hasil ekspresi gen dengan rumus Livak.
Hasil: Hasil penelitian menunjukkan sel kanker payudara yang diberi perlakuan mengekspresikan 1,36 kali lipat lebih tinggi dibandingkan sel kelompok kontrol untuk mengekspresikan protein anti-apoptosis BCL-2. Hasil penelitian juga menunjukkan perbedaan yang bermakna antara kelompok perlakuan dan kontol untuk ekspresi gen BCL-2 continous cell T47D kanker payudara dengan nilai p=0,002 (p<0,005).
Pembahasan: Asetogenin adalah inhibitor kuat dari NADH dehidrogenase yang dapat menurunkan produksi ATP yang dapat menyebabkan kematian pada sel kanker. Pada inhibisi ini dapat memicu adanya aktivasi pada jalur apoptosis dan pengaktifan gen p53 dengan target gen BCL-2 yang dapat menghentikan siklus dari sel yang akan mencegah proliferasi yang tidak terkendali.
Simpulan: Terdapat perbedaan yang signifikan dan bermakna pada nilai cycle quantification RT-PCR gen BCL-2 pada sel kelompok menggunakan ekstrak daun sirsak dan kontrol. Selain itu, ekstrak daun sirsak yang mengandung asetogenin tidak efektif dalam menurunkan kadar ekspresi gen anti-apoptosis BCL-2 pada continous cell T47D kanker payudara.
Kata kunci: Asetogenin, Continous cell T47D, Ekstrak daun sirsak, Gen BCL-2, RT-PCR.
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Referensi
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22. Hussaana A, Djam’an Q, Goenarwo E. Ekstrak daun Sirsak (annona muricata) sebagai penghambat perkembangan tumor payudara. J Farm Sains dan Terap. 2015;2:41-4.
23. O’Brien MA, Kirby R. Apoptosis: A review of pro-apoptotic and anti-apoptotic pathways and dysregulation in disease. J Vet Emerg Crit Care. 2018;18:572-85.
24. Fidianingsih I, Handayani ES. Annona muricata aqueous extract suppresses T47D breast cancer cell proliferation. Universa Med. 2014;33:19-26
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27. Jacobo-Herrera N, Pérez-Plasencia C, Castro-Torres VA, Martínez-Vázquez M, González-Esquinca AR, Zentella-Dehesa. A selective acetogenins and their potential as anticancer agents. Front Pharmacol. 2019;10:1-12.
28. Tsujimoto Y. Role of Bcl-2 family proteins in apoptosis: Apoptosomes or mitochondria?. Genes to Cells. 1998;3:697-707.
29. Yarsi J. Protein kelompok BCI-2sebagai target senyawa antikanker BCI-2- family proteins as target of anticancer drug. 2016;14:238-42.
30. Izabella D, Magdalena K, Rafal S. Evaluation of apoptosis-associated protein (Bcl-2, Bax, cleaved caspase-3 and p53) expression in canine mammary tumors: an immunohistochemical and prognostic study. Elsevier. 2016;16:1-37.
31. Chin Y, Kinghorn AD. Structural characterization, biological effects, and synthetic studies on xanthones from mangosteen (Garcinia mangostana), a popular botanical dietary supplement. Mini Rev. Org. Chem. 2018;5:355-64.
32. Orozco GF, Chitchumroonchokchai C, Lesinski G, Suksamrarn S, Failla M. α-Mangostin: Anti-inflammatory activity and metabolism by human cells. J. Agric. Food Chem. 2013;61:3891-900.
33. Joseph F, Tomashefski JR, Philip TC, Carol FF, Armando EF. Dall and hammars : neoplastic lung disease. New York: Springer; 2016. p.21.
34. Dai H, Meng W, Kaufmann S. BCL2 family, mitochondrial apoptosis, and beyond. Cancer Transl Med. 2016;2:7.
35. Vartiainen S. Caenorhabditis elegans. Encycl Mov Disord. 2010;3:171-73
36. Wong R. Apoptosis in cancer: From pathogenesis to treatment. J Exp Clin Canc Res. 2011;30:1-14.
37. Kumar V, Cotran RS, Robbins SL. Buku ajar patologi robbins/ Vinay Kumar; alih bahasa, Ening krisnuhoni; editor edisi Bahasa Indonesia, I Made Nasar, Santoso Cornain. Jakarta: Penerbit Buku Kedokteran EGC; 2013. p.16-20.
38. Sari LM. Mekanisme molekuler kematian sel. Cakradonya Dent J. 2018;10:65-70.
39. Pistritto G, Trisciuoglio D, Ceci C, Alessia G, D’Orazi G. Apoptosis as anticancer mechanism: Function and dysfunction of its modulators and targeted therapeutic strategies. Aging (Albany NY). 2016;8:603-19.
40. Indrasetiawan P, Astuti I. Activity of -terpineol as a potential anticancer candidate: cytotoxicity, proapoptotic and antiproliferative evaluation in TD47 cell lines. J Med Sci (Berkala Ilmu Kedokteran). 2015;44:10-7.
41. Dencic SM, Poljarevic J, Vilimanovich U. Cyclohexyl analogues of ethylenediamine dipropanoic acid induce caspase-independent mitochondrial apoptosis in human leukemic cells. Chem Res Toxicol. 2012;25:931-9.
42. Nikoletopoulou V, Markaki M, Palikaras K, Tavernarakis N. Crosstalk between apoptosis, necrosis and autophagy. Biochim Biophys Acta-Mol Cell Res. 2013;1833:3448-59.
43. Looi CY, Moharram B, Paydar M, Arya A, Leong KH, Mohamad K. Induction of apoptosis in melanoma A375 cells by a chloroform fraction of centratherum anthelminticum (L.) seeds involves NF-kappaB, p53 and Bcl-2-controlled mitochondrial signaling pathways. BMC Complem Altern M. 2017;13:166-8.
44. Yahaya G. Phytochemical screening, anti-oxidant activity and in vitro anticancer potensial of ethanolic and water leaves extracts of Annona muricata (Graviola). Asian Pac J Trop Med. 2014;7:355-63.
45. Adewole SO, Caxton MEA. Morphological changes and hypoglycemic effects of annona muricata Linn.(annonaceae) leaf aqueous extract on pancreatic β-cells of streptozotocin-treated diabetic rats. Afr J Biomed Res 2016;9:173-87.
46. Chatterjee S, Ovadje P, Griffin C, Tran C, Hamm C, Pandey S. Selective induction of apoptosis through activation of caspase-8 in human leukemia cells (Jurkat) by dandelion root extract. J Ethnopharmacol. 2021;133:86–91.
47. Lienggonegoro LA. Soursop leaf (Annona muricata) and it is potential as an anti-cancer. Pros Sem Nas Masy Biodiv Indon. 2020;6:653-7.
48. Saelens X, Festjens N, Walle LV, Grup MV, Loo GV, Vandenabeele P. Toxic proteins released from mitochondria in cell death. Oncogene. 2012;23:2861-74.
49. Boskovic ZV, Adams DJ, Theriault JR, Wang AJ, Stern AM, Wagner BK, et.al. High-throughput screening identifies small-molecule enhancers of reactive oxygen species that are nontoxic or cause genotype-selective cell death. ACS Chem Biol. 2013;8:923-9.
50. Gellerich FN, Trumbeckaite S, Opaika JR, Seppet E, Rasmussen HN, Neuhoff C, et.al. Function of the mitochondrial outer membrane as a diffusion barrier in health and diseases. Biochem Soc Trans. 2020;28:164-9.
51. Aisha SD, Hetal B, Bryan L, David WA. BH-3 only proteins : orchestrators of apoptosis. BBACMR. 2014;11:508-20.
2. Sergiusz L, Marcin C, Alicja F, Jacek B, Robert S, Andrzej S. Breast Cancer-Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies-An Updated Review. Cancers. 2021;13:4287-93.
3. GLOBOCAN (2020c). International Agency for Research on Cancer : Estimated number of new cases from 2020 to 2040, both sexes, age [85+] [Internet]. 2020 [cited 2022 Mar 25]. Available from: https://gco.iarc.fr/tomorrow/en/dataviz/isotype?years=2040&single_unit=5 00000&cancers=20
4. World Health Organization. Global Health Estimates 2016: Disease Burden by Cause, Age, Sex, by Country and by Region, 2000–2016; World Health Organization: Geneva, Switzerland, 2018; Available online: https://www.who.int/healthinfo/global_burden_ disease/esti-mates/en/index1.html (accessed on March, 25th 2022).
5. Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, et.al. Global Cancer Observatory Cancer Today. Lyon: International Agency for Research on Cancer; 2020.
6. Ginsburg O, Bray F, Coleman M, Vanderpuye V, Eniu A, Kotha SR, et.al. The global burden of women’s cancers: A grand challenge in global health. Lancet. 2016;389:847-60.
7. Vostakolaei FA, Karim-Kos HE, Janssen-Heijnen MLG, Visser O, Verbeek ALM, Kiemeney L. The validity of the mortality to incidence ratio as a proxy for site-specific cancer survival. Eur J Public Health. 2010;21:573-77.
8. Ferlay J, Laversanne M, Ervik M, Lam F, Colombet M, Mery L, et.al. Global Cancer Observatory: Cancer Tomorrow. New York: International Agency for Research on Cancer; 2020.
9. Sharma, R. Breast cancer incidence, mortality and mortality-to-incidence ratio (MIR) are associated with human development, 1990–2016: Evidence from Global Burden of Disease Study 2016. Breast Cancer. 2019;26:428-45.
10. Mugi W, Sofia H, Vita A, Rini N. Population based cancer registration in Indonesia. Asian Pasific Journal of Cancer Prevention : APJCP. 2021;13:1709-10.
11. Badan Penelitian dan Pengembangan Kesehatan Kementerian Kesehatan RI. Riset kesehatan dasar (RISKESDAS) tahun 2018. http:// https://www.kemkes.go.id/resources/download/info-terkini/hasil-riskesdas2018.pdf.
12. Gani. Tumor ganas. J Poltekes Jogja. 2017: hal.6-25.
13. Rumah Sakit Umum Pusat (RSUP) Dr.M.Djamil. 2021. Data kunjungan pasien rawat jalan di RSUP Dr M Djamil Padang tahun 2017-2021 di Poliklinik Bedah Padang. Instansi Rekam Medik RSUP Dr M Djamil Padang.
14. Adelina R, Febrianti R, Oktoberia IS, Intan PR. Ekstrak daun annona muricata linn sebagai antiproliferasi terhadap sel hepar tikus terinduksi 7,12 dimetilbenz [a] antracene (DMBA). Kefarmasian Indonesia. 2015;4:1-12.
15. Chitwood K, Etzkorn J, Cohen G. Topical and intralesional treatment of nonmelanoma skin cancer: Efficacy and cost comparisons. Dermatologic Surgery. 2013;39:1306-16.
16. Harahap WA. Pembedahan Pada Tumor Ganas Payudara. Maj Kedokt Andalas. 2015;38:57.
17. Puspitasari ML. Aktivitas antioksidan suplemen herbal daun sirsak (Annona muricata L.) dan kulit manggis (Garcinia mangostana l.). J Pangan dan Agroindustri. 2016;4:283–90.
18. Puspita EW, Pujiasih. Efek ekstrak metanol daun sirsak (annona muricata linn) terhadap pertumbuhan kanker payudara mencit C3H. Buletin Penelitian Kesehatan. 2014;3:17-23.
19. Latief A. Obat tradisional. Jakarta: EGC; 2012
20. Retnani V, Prajoko YW. Pengaruh suplementasi ekstrak daun annona muricata terhadap kejadian displasia epitel kelenjar payudara tikus sprague dawley yang diinduksi 7,12 dimethylbenz (a) anthracene. Artikel Ilmiah Sarjana Kedokteran Universitas Diponegoro. 2011.
21. Muhartono, Subekti. Penggunaan ekstrak daun sirsak sebagai obat kemoterapi kanker payudara. Prosiding Seminar Presentasi Artikel Ilmiah Dies Natalis FK Unila ke 13. 2015;3:1-8.
22. Hussaana A, Djam’an Q, Goenarwo E. Ekstrak daun Sirsak (annona muricata) sebagai penghambat perkembangan tumor payudara. J Farm Sains dan Terap. 2015;2:41-4.
23. O’Brien MA, Kirby R. Apoptosis: A review of pro-apoptotic and anti-apoptotic pathways and dysregulation in disease. J Vet Emerg Crit Care. 2018;18:572-85.
24. Fidianingsih I, Handayani ES. Annona muricata aqueous extract suppresses T47D breast cancer cell proliferation. Universa Med. 2014;33:19-26
25. Dewson G, Kluck RM. Bcl-2 family regulated apoptosis in health and disease. Cell Health and Cytoskeleton. 2010. p. 9–22.
26. Arisanty D. In vitro cytotoxic study and detection of apoptosis on breast cancer cell lines mda-mb 231 after exposed to azadirachta indica a. juss (neem) extract. J Kesehat Andalas. 2013;2:80.
27. Jacobo-Herrera N, Pérez-Plasencia C, Castro-Torres VA, Martínez-Vázquez M, González-Esquinca AR, Zentella-Dehesa. A selective acetogenins and their potential as anticancer agents. Front Pharmacol. 2019;10:1-12.
28. Tsujimoto Y. Role of Bcl-2 family proteins in apoptosis: Apoptosomes or mitochondria?. Genes to Cells. 1998;3:697-707.
29. Yarsi J. Protein kelompok BCI-2sebagai target senyawa antikanker BCI-2- family proteins as target of anticancer drug. 2016;14:238-42.
30. Izabella D, Magdalena K, Rafal S. Evaluation of apoptosis-associated protein (Bcl-2, Bax, cleaved caspase-3 and p53) expression in canine mammary tumors: an immunohistochemical and prognostic study. Elsevier. 2016;16:1-37.
31. Chin Y, Kinghorn AD. Structural characterization, biological effects, and synthetic studies on xanthones from mangosteen (Garcinia mangostana), a popular botanical dietary supplement. Mini Rev. Org. Chem. 2018;5:355-64.
32. Orozco GF, Chitchumroonchokchai C, Lesinski G, Suksamrarn S, Failla M. α-Mangostin: Anti-inflammatory activity and metabolism by human cells. J. Agric. Food Chem. 2013;61:3891-900.
33. Joseph F, Tomashefski JR, Philip TC, Carol FF, Armando EF. Dall and hammars : neoplastic lung disease. New York: Springer; 2016. p.21.
34. Dai H, Meng W, Kaufmann S. BCL2 family, mitochondrial apoptosis, and beyond. Cancer Transl Med. 2016;2:7.
35. Vartiainen S. Caenorhabditis elegans. Encycl Mov Disord. 2010;3:171-73
36. Wong R. Apoptosis in cancer: From pathogenesis to treatment. J Exp Clin Canc Res. 2011;30:1-14.
37. Kumar V, Cotran RS, Robbins SL. Buku ajar patologi robbins/ Vinay Kumar; alih bahasa, Ening krisnuhoni; editor edisi Bahasa Indonesia, I Made Nasar, Santoso Cornain. Jakarta: Penerbit Buku Kedokteran EGC; 2013. p.16-20.
38. Sari LM. Mekanisme molekuler kematian sel. Cakradonya Dent J. 2018;10:65-70.
39. Pistritto G, Trisciuoglio D, Ceci C, Alessia G, D’Orazi G. Apoptosis as anticancer mechanism: Function and dysfunction of its modulators and targeted therapeutic strategies. Aging (Albany NY). 2016;8:603-19.
40. Indrasetiawan P, Astuti I. Activity of -terpineol as a potential anticancer candidate: cytotoxicity, proapoptotic and antiproliferative evaluation in TD47 cell lines. J Med Sci (Berkala Ilmu Kedokteran). 2015;44:10-7.
41. Dencic SM, Poljarevic J, Vilimanovich U. Cyclohexyl analogues of ethylenediamine dipropanoic acid induce caspase-independent mitochondrial apoptosis in human leukemic cells. Chem Res Toxicol. 2012;25:931-9.
42. Nikoletopoulou V, Markaki M, Palikaras K, Tavernarakis N. Crosstalk between apoptosis, necrosis and autophagy. Biochim Biophys Acta-Mol Cell Res. 2013;1833:3448-59.
43. Looi CY, Moharram B, Paydar M, Arya A, Leong KH, Mohamad K. Induction of apoptosis in melanoma A375 cells by a chloroform fraction of centratherum anthelminticum (L.) seeds involves NF-kappaB, p53 and Bcl-2-controlled mitochondrial signaling pathways. BMC Complem Altern M. 2017;13:166-8.
44. Yahaya G. Phytochemical screening, anti-oxidant activity and in vitro anticancer potensial of ethanolic and water leaves extracts of Annona muricata (Graviola). Asian Pac J Trop Med. 2014;7:355-63.
45. Adewole SO, Caxton MEA. Morphological changes and hypoglycemic effects of annona muricata Linn.(annonaceae) leaf aqueous extract on pancreatic β-cells of streptozotocin-treated diabetic rats. Afr J Biomed Res 2016;9:173-87.
46. Chatterjee S, Ovadje P, Griffin C, Tran C, Hamm C, Pandey S. Selective induction of apoptosis through activation of caspase-8 in human leukemia cells (Jurkat) by dandelion root extract. J Ethnopharmacol. 2021;133:86–91.
47. Lienggonegoro LA. Soursop leaf (Annona muricata) and it is potential as an anti-cancer. Pros Sem Nas Masy Biodiv Indon. 2020;6:653-7.
48. Saelens X, Festjens N, Walle LV, Grup MV, Loo GV, Vandenabeele P. Toxic proteins released from mitochondria in cell death. Oncogene. 2012;23:2861-74.
49. Boskovic ZV, Adams DJ, Theriault JR, Wang AJ, Stern AM, Wagner BK, et.al. High-throughput screening identifies small-molecule enhancers of reactive oxygen species that are nontoxic or cause genotype-selective cell death. ACS Chem Biol. 2013;8:923-9.
50. Gellerich FN, Trumbeckaite S, Opaika JR, Seppet E, Rasmussen HN, Neuhoff C, et.al. Function of the mitochondrial outer membrane as a diffusion barrier in health and diseases. Biochem Soc Trans. 2020;28:164-9.
51. Aisha SD, Hetal B, Bryan L, David WA. BH-3 only proteins : orchestrators of apoptosis. BBACMR. 2014;11:508-20.
Diterbitkan
2023-04-11
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MAHENDIKA, Devin; DARNEZ, Luthfi.
PENGARUH PEMBERIAN EKSTRAK DAUN SIRSAK (Annona muricata Linn) TERHADAP GEN ANTI APOPTOSIS BCL-2 CONTINOUS CELL T47D PADA KANKER PAYUDARA.
Essence of Scientific Medical Journal, [S.l.], v. 20, n. 2, p. 1-11, apr. 2023.
ISSN 2655-6472.
Tersedia pada: <http://103.29.196.112/index.php/essential/article/view/85245>. Tanggal Akses: 04 mar. 2026
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