Melatonin Modulation of Radiation and Chemotherapeutics-induced Changes on Differentiation of Breast Fibroblasts

Melatonin exerts oncostatic actions and sensitizes tumor cells to chemotherapeutics or radiation. In our study, we investigated the e ects of docetaxel, vinorelbine, and radiation on human breast fibroblasts and its modulation by melatonin. Docetaxel or vinorelbine inhibits proliferation and stimulates the di erentiation of breast preadipocytes, by increasing C/EBP and PPAR expression and by downregulating tumor necrosis factor (TNF ), interleukin 6 (IL-6), and IL-11 expression. Radiation inhibits both proliferation and di erentiation through the downregulation of C/EBP and PPAR and by stimulating TNF expression. In addition, docetaxel and radiation decrease aromatase activity and expression by decreasing aromatase promoter II and cyclooxygenases 1 and 2 (COX-1 and COX-2) expression. Melatonin potentiates the stimulatory e ect of docetaxel and vinorelbine on di erentiation and their inhibitory e ects on aromatase activity and expression, by increasing the stimulatory e ect on C/EBP and PPAR expression and the downregulation of antiadipogenic cytokines and COX expression. Melatonin also counteracts the inhibitory e ect of radiation on di erentiation of preadipocytes, by increasing C/EBP and PPAR expression and by decreasing TNF expression. Melatonin also potentiates the inhibitory e ect exerted by radiation on aromatase activity and expression by increasing the downregulation of promoter II, and COX-1 and COX-2 expression. Our findings suggest that melatonin modulates regulatory e ects induced by chemotherapeutic drugs or radiation on preadipocytes, which makes it a promising adjuvant for chemotherapy and radiotherapy sensibilization.Funding: This work was supported by a grant from the Spanish Economy and Competitiveness Ministry (SAF2016-77103-P) and from Instituto de Investigación Sanitaria Valdecilla (IDIVAL) (APG/12)