Melatonin and 5-fluorouracil combination chemotherapy: opportunities and efficacy in cancer therapy

Abstract

Combined chemotherapy is a treatment method based on the simultaneous use of two or more therapeutic agents; it is frequently necessary to produce a more effective treatment for cancer patients. Such combined treatments often improve the outcomes over that of the monotherapy approach, as the drugs synergistically target critical cell signaling pathways or work independently at different oncostatic sites. A better prognosis has been reported in patients treated with combination therapy than in patients treated with single drug chemotherapy. In recent decades, 5-fluorouracil (5-FU) has become one of the most widely used chemotherapy agents in cancer treatment. This medication, which is soluble in water, is used as the first line of anti-neoplastic agent in the treatment of several cancer types including breast, head and neck, stomach and colon cancer. Within the last three decades, many studies have investigated melatonin as an anti-cancer agent; this molecule exhibits various functions in controlling the behavior of cancer cells, such as inhibiting cell growth, inducing apoptosis, and inhibiting invasion. The aim of this review is to comprehensively evaluate the role of melatonin as a complementary agent with 5-FU-based chemotherapy for cancers. Additionally, we identify the potential common signaling pathways by which melatonin and 5-FU interact to enhance the efficacy of the combined therapy. Video abstract.

Keywords: 5-fluorouracil; Chemotherapy; Combination therapy; Melatonin.

Fig. 1

A schematic view of the combination therapy of melatonin and 5-FU in regulating the signaling pathways of cancer cells. The combination therapy of melatonin and 5-FU can lead to effects such as induction of apoptosis, increasing the sensitivity of cells to 5-FU and inhibition of cell growth through different signaling pathways. Red blocked-end arrow illustrate inhibition and black arrow show stimulation and/or activation. Blue down arrow: decrease, blue up arrow: increase. Abbreviations: ROS, Reactive oxygen species; XIAP, X-linked inhibitor of apoptosis protein; GSK3β, Glycogen synthase kinase 3β; NF-κB, Nuclear factor κB; iNOS, Inducible nitric oxide synthase; Oct4, Octamer-binding transcription factor 4 TYMS, Thymidylate synthetase