MELATONIN DAN APOPTOSIS PADA KANKER PAYUDARA : SEBUAH TINJAUAN SISTEMATIS
DOI:
https://doi.org/10.31004/prepotif.v9i3.52281Keywords:
apoptosis, kanker payudara, melatoninAbstract
Kanker payudara merupakan keganasan tersering pada wanita dan menjadi penyebab utama kematian terkait kanker di seluruh dunia. Heterogenitas biologis kanker payudara memengaruhi respon terapi dan prognosis. Salah satu pendekatan penting dalam pengobatan kanker adalah induksi apoptosis, mengingat disregulasi jalur kematian sel berperan besar dalam proliferasi sel tumor yang tidak terkontrol. Melatonin, hormon endogen yang diproduksi terutama oleh kelenjar pineal, telah banyak diteliti karena sifat antioksidan dan efek antikankernya. Untuk itu, tinjauan ini bertujuan untuk merangkum hasil penelitian yang menilai efek apoptosis dari melatonin pada kanker payudara. Tinjauan sistematis ini dilakukan sesuai dengan kriteria PRISMA. Data dikumpulkan dari database PubMed dan ScienceDirect mulai Januari 2015 hingga Oktober 2025. Sebanyak 14 artikel yang ditinjau terdiri dari dua penelitian in vivo dan 13 in vitro. Jenis sel kanker yang diteliti meliputi positif reseptor ER, reseptor ER dan PR, HER2-overexpression, dan TNBC. Studi menunjukkan peningkatan apoptosis sel kanker payudara setelah pemberian melatonin, baik tunggal maupun kombinasi dengan agen lainnya secara in vitro maupun in vivo. Mekanisme apoptosis yang dimediasi melatonin melibatkan peningkatan stres oksidatif, induksi stres retikulum endoplasma, modulasi jalur inflamasi, serta inhibisi jalur survival sel seperti PI3K/Akt/mTOR. Melatonin juga memengaruhi keseimbangan protein pro-apoptotik dan anti-apoptotik, termasuk peningkatan Bax, caspase-3/9, serta penurunan Bcl-2 dan survivin. Respon apoptosis tertinggi ditemukan pada subtipe kanker payudara positif ER, menunjukkan bahwa status hormonal berperan penting dalam efektivitas melatonin. Namun, masih dibutuhkan penelitian lebih lanjut untuk membandingkan efek dan mekanisme apoptosis antara berbagai subtipe kanker payudara.References
Alanazi, R. J., Fallatah, D. I., Helal, G., Alqarni, A. M., Aloraini, G. S., Alonazi, F. N., Alrabia, M. W., Alruwaili, A. M., & Alenzi, F. Q. B. (2022). Close link between breast cancer & apoptosis. International Journal of Health Sciences, 10446–10456. https://doi.org/10.53730/ijhs.v6ns6.12757
Alonso-González, C., Menéndez-Menéndez, J., González-González, A., González, A., Cos, S., & Martínez-Campa, C. (2018). Melatonin enhances the apoptotic effects and modulates the changes in gene expression induced by docetaxel in MCF-7 human breast cancer cells. International Journal of Oncology, 52(2), 560–570. https://doi.org/10.3892/ijo.2017.4213
Das, N., Mukherjee, S., Das, A., Gupta, P., Bandyopadhyay, A., & Chattopadhyay, S. (2024). Intra-tumor ROS amplification by melatonin interferes in the apoptosis-autophagy-inflammation-EMT collusion in the breast tumor microenvironment. Heliyon, 10(1). https://doi.org/10.1016/j.heliyon.2023.e23870
Demirkesen, Ş., İriağaç, Y., Şeber, E. S., & Aral, C. (2025). Melatonin enhances everolimus efficacy in breast cancer by suppressing mTOR pathway activation and promoting apoptosis and mitochondrial function. BMC Pharmacology and Toxicology , 26(1). https://doi.org/10.1186/s40360-025-00907-1
Elmore, S. (2007). Apoptosis: A Review of Programmed Cell Death. Toxicologic Pathology, 35(4), 495–516. https://doi.org/10.1080/01926230701320337
Estirado, S., Fernández-Delgado, E., Viñuelas-Zahínos, E., Luna-Giles, F., Rodríguez, A. B., Pariente, J. A., & Espino, J. (2022). Pro-Apoptotic and Anti-Migration Properties of a Thiazoline-Containing Platinum(II) Complex in MDA-MB-231 Breast Cancer Cells: The Role of Melatonin as a Synergistic Agent. Antioxidants, 11(10). https://doi.org/10.3390/antiox11101971
Gatti, G., Lucini, V., Dugnani, S., Calastretti, A., Spadoni, G., Bedini, A., Rivara, S., Mor, M., Canti, G., Scaglione, F., & Bevilacqua, A. (2017). Antiproliferative and pro-apoptotic activity of melatonin analogues on melanoma and breast cancer cells. Oncotarget, 8(40), 68338–68353. www.impactjournals.com/oncotarget/
Grant, S. G., Melan, M. A., Latimer, J. J., & Witt-Enderby, P. A. (2009). Melatonin and breast cancer: Cellular mechanisms, clinical studies and future perspectives. In Expert Reviews in Molecular Medicine (Vol. 11). https://doi.org/10.1017/S1462399409000982
Kadam, C. Y., & Abhang, S. A. (2016). Apoptosis Markers in Breast Cancer Therapy. In Advances in Clinical Chemistry (1st ed., Vol. 74). Elsevier Inc. https://doi.org/10.1016/bs.acc.2015.12.003
Kaloni, D., Diepstraten, S. T., Strasser, A., & Kelly, G. L. (2023). BCL-2 protein family: attractive targets for cancer therapy. Apoptosis, 28(1–2), 20–38. https://doi.org/10.1007/s10495-022-01780-7
Kamfar, W. W., Khraiwesh, H. M., Ibrahim, M. O., Qadhi, A. H., Azhar, W. F., Ghafouri, K. J., Alhussain, M. H., Aldairi, A. F., AlShahrani, A. M., Alghannam, A. F., Abdulal, R. H., Al-Slaihat, A. H., Qutob, M. S., Elrggal, M. E., Ghaith, M. M., & Azzeh, F. S. (2024). Comprehensive review of melatonin as a promising nutritional and nutraceutical supplement. In Heliyon (Vol. 10, Issue 2). Elsevier Ltd. https://doi.org/10.1016/j.heliyon.2024.e24266
Koşar, P. A., Nazıroğlu, M., Övey, İ. S., & Çiğ, B. (2016). Synergic Effects of Doxorubicin and Melatonin on Apoptosis and Mitochondrial Oxidative Stress in MCF-7 Breast Cancer Cells: Involvement of TRPV1 Channels. Journal of Membrane Biology, 249(1–2), 129–140. https://doi.org/10.1007/s00232-015-9855-0
Li, M., Wu, C., Muhammad, J. S., Yan, D., Tsuneyama, K., Hatta, H., Cui, Z. G., & Inadera, H. (2020). Melatonin sensitises shikonin-induced cancer cell death mediated by oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway. Redox Biology, 36. https://doi.org/10.1016/j.redox.2020.101632
Maroufi, N. F., Rashidi, M., Vahedian, V., Jahanbazi, R., Mostafaei, S., Akbarzadeh, M., Kazemzadeh, H., Nejabati, H. R., Isazadeh, A., Rashidi, M. R., & Nouri, M. (2022). Effect of Apatinib plus melatonin on vasculogenic mimicry formation by cancer stem cells from breast cancer cell line. Breast Cancer, 29(2), 260–273. https://doi.org/10.1007/s12282-021-01310-4
Motehaver, A. N., Sheida, F., Javadinia, S. A., Behzadi, B., Afshar, S., Khezrian, A., Ganjuri, M., Eslah, S., Mokhles, P., Keshtpour Amlashi, Z., & Akbari, M. E. (2025). Melatonin and Breast Cancer: A Review Article. Chonnam Medical Journal, 61(2), 63. https://doi.org/10.4068/cmj.2025.61.2.63
Peng, Y., Wang, Y., Zhou, C., Mei, W., & Zeng, C. (2022). PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway? In Frontiers in Oncology (Vol. 12). Frontiers Media S.A. https://doi.org/10.3389/fonc.2022.819128
Prabhu, K. S., Kuttikrishnan, S., Mariyam, Z., Habeeba, U., Panicker, A. J., Masoodi, T., Junejo, K., & Uddin, S. (2025). PI3 K/AKT/mTOR pathway and its role in breast cancer stem cells. In Naunyn-Schmiedeberg’s Archives of Pharmacology. Springer Science and Business Media Deutschland GmbH. https://doi.org/10.1007/s00210-025-04297-3
Qian, J., Zhao, L., Xu, L., Zhao, J., Tang, Y., Yu, M., Lin, J., Ding, L., & Cui, Q. (2024). Cell Death: Mechanisms and Potential Targets in Breast Cancer Therapy. In International Journal of Molecular Sciences (Vol. 25, Issue 17). Multidisciplinary Digital Publishing Institute (MDPI). https://doi.org/10.3390/ijms25179703
Qian, S., Wei, Z., Yang, W., Huang, J., Yang, Y., & Wang, J. (2022). The role of BCL-2 family proteins in regulating apoptosis and cancer therapy. Frontiers in Oncology, 12(October), 1–16. https://doi.org/10.3389/fonc.2022.985363
Rajabi, A., Safaralizadeh, R., Saber, A., Pourmahdi, M., Teimourian, S., Montazeri, V., Fakhrjou, A., & Hosseinpourfeizi, M. (2025). Apoptotic effect of melatonin on ER-positive breast cancer cell lines: ADGRL4 gene expression and promoter methylation. Naunyn-Schmiedeberg’s Archives of Pharmacology, 398(2), 1815–1823. https://doi.org/10.1007/s00210-024-03383-2
Safaroghli-Azar, A., Pourbagheri-Sigaroodi, A., Bashash, D., Nooshinfar, E., Anjam-Najmedini, A., Sadeghi, S., Rezaie-Tavirani, M., & Akbari, M. E. (2018). Stimulatory Effect of Indolic Hormone on As2O3 Cytotoxicity in Breast Cancer Cells: NF-κB-dependent Mechanism of Action of Melatonin.
Sang, X., Li, L., Rui, C., Liu, Y., Liu, Z., Tao, Z., Cheng, H., & Liu, P. (2021). Induction of EnR stress by Melatonin enhances the cytotoxic effect of Lapatinib in HER2-positive breast cancer. Cancer Letters, 518, 82–93. https://doi.org/10.1016/j.canlet.2021.06.011
Smolarz, B., Zadrożna Nowak, A., & Romanowicz, H. (2022). Breast Cancer—Epidemiology, Classification, Pathogenesis and Treatment (Review of Literature). In Cancers (Vol. 14, Issue 10). MDPI. https://doi.org/10.3390/cancers14102569
Talib, W. H., Alsayed, A. R., Abuawad, A., Daoud, S., & Mahmod, A. I. (2021). Melatonin in cancer treatment: Current knowledge and future opportunities. In Molecules (Vol. 26, Issue 9). MDPI AG. https://doi.org/10.3390/molecules26092506
Tran, Q. H., Hoang, D. H., Song, M., Choe, W., Kang, I., Kim, S. S., & Ha, J. (2021). Melatonin and doxorubicin synergistically enhance apoptosis via autophagy-dependent reduction of AMPKα1 transcription in human breast cancer cells. Experimental and Molecular Medicine, 53(9), 1413–1422. https://doi.org/10.1038/s12276-021-00675-y
Upadhyay, K., Patel, F., Robin, E., Ramachandran, A. V., & Baxi, D. (2025). In-vitro Analysis of Solanum virginianum L. Extract and Melatonin: Synergistic Induction of Apoptosis in MDA-MB-231 Breast Cancer Cells. Applied Biochemistry and Biotechnology. https://doi.org/10.1007/s12010-025-05335-9
Weisz, L., Damalas, A., Liontos, M., Karakaidos, P., Fontemaggi, G., Maor-Aloni, R., Kalis, M., Levrero, M., Strano, S., Gorgoulis, V. G., Rotter, V., Blandino, G., & Oren, M. (2007). Mutant p53 enhances nuclear factor κB activation by tumor necrosis factor α in cancer cells. Cancer Research, 67(6), 2396–2401. https://doi.org/10.1158/0008-5472.CAN-06-2425
WHO. (2024). Breast Cancer. WHO. https://www.who.int/news-room/fact-sheets/detail/breast-cancer
Yuan, S., Norgard, R. J., & Stanger, B. Z. (2019). Cellular plasticity in cancer. In Cancer Discovery (Vol. 9, Issue 7, pp. 837–851). American Association for Cancer Research Inc. https://doi.org/10.1158/2159-8290.CD-19-0015
Yun, S. M., Woo, S. H., Oh, S. T., Hong, S. E., Choe, T. B., Ye, S. K., Kim, E. K., Seong, M. K., Kim, H. A., Noh, W. C., Lee, J. K., Jin, H. O., Lee, Y. H., & Park, I. C. (2016). Melatonin enhances arsenic trioxide-induced cell death via sustained upregulation of Redd1 expression in breast cancer cells. Molecular and Cellular Endocrinology, 422, 64–73. https://doi.org/10.1016/j.mce.2015.11.016
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