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Life Sci. 2019 Jul 1;228:228-241. doi: 10.1016/j.lfs.2019.05.009. Epub 2019 May 8.

Modulation of apoptosis by melatonin for improving cancer treatment efficiency: An updated review.

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Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran. Electronic address:
Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran. Electronic address:
Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, 48175-861, Iran. Electronic address:
Department of Morphology and Cell Biology, Faculty of Medicine, University of Oviedo, C/ Julián Clavería 6, 33006, Oviedo, Spain.
Department of Physiology, College of Medicine, University of Misan, Misan, Iraq.
Research Center for Molecular and Cellular Imaging, Tehran University of Medical Sciences (International Campus), Tehran, Iran.


Radio- and chemotherapy are the most common cancer treatment modalities. They cause acute and late side effects on normal tissues, which is a burden for delivery of a high dose of radiation or drugs on tumor cells. In addition, tumor cells achieve adaptive responses to subsequent doses of radiation and chemotherapy, leading to tumor resistance and accelerated repopulation. Resistance to radiotherapy and chemotherapy can occur following adaptive responses, which itself is due to the release of large numbers of inter- and intracellular mediators by immune cells as well as other tumor microenvironment (TME) cells. Melatonin is a potent natural antioxidant and anti-inflammatory agent that protects against toxic side effects of radiation and chemotherapy. Furthermore, in some cancer cells, melatonin aids sensitizing cancer cells to therapy. Apoptosis is one of the main mechanisms of cell death following exposure to radiation and chemotherapy. Evidences have shown a direct relation between apoptosis induction in tumor cells with increased tumor delay regression and survival. Melatonin through modulation of several apoptosis mediators such as mitochondria, Bax, Bcl-2, endogenous ROS, and apoptosis receptors facilitate apoptosis. The current review aims to explain mechanisms of apoptosis induction following exposure to radiation and chemotherapy drugs. We also reviewed the modulatory effect of melatonin on apoptosis signaling pathways.


Apoptosis; COX-2; Chemotherapy; Hypoxia; MAPKs; Melatonin; Mitochondria; NF-κB; Neoplasm; Radiation; Radiotherapy; Tumor Microenvironment (TME)

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