• Wamidh H Talib.
• Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman, Jordan. Electronic address: w_talib@asu.edu.jo.
• Nutrition. 2020 Apr 1; 72: 110659.

ObjectivesChemotherapy is one of the major treatments of cancer. However, the emergence of resistance to chemotherapeutic agents is still a major obstacle in the successful management of resistant tumors. Therefore, development of new mechanisms to overcome drug resistance is essential and may be further developed into effective therapies that can flip the switch from drug resistance to susceptibility. The aim of this study was to evaluate a combination consisting of a ketogenic diet and melatonin to determine whether it would inhibit cisplatin- and vincristine-resistant breast cancer.MethodsIn the in vitro part of the study, drug-resistant cell lines were treated with melatonin and real-time polymerase chain reaction was used to measure levels of gene expression involved in apoptosis and resistance. On the protein level, the activity of caspase-3 and the level of vascular endothelin growth factor protein were determined. In the in vivo part, tumor-bearing mice received one of the following treatments: ketogenic diet, melatonin, combination of melatonin and ketogenic diet, vehicle, or chemotherapy.ResultsSuccessful inhibition of resistant cell lines was achieved by melatonin. This inhibition was mediated by induction of apoptosis, inhibition of angiogenesis, and downregulation of resistance genes. A synergistic anticancer effect was observed between melatonin and the ketogenic diet against resistant breast tumors inoculated in mice with a cure rate of 70%.ConclusionsThe combination of melatonin and a ketogenic diet represents a promising option to overcome drug resistance in cancer chemotherapy. However, further testing on the protein level using flow cytometry is important to better understand the mechanisms of action.Copyright © 2019 Elsevier Inc. All rights reserved.

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