Abstract
Melatonin exerts oncostatic actions and sensitizes tumor cells to chemotherapeutics or radiation. In our study, we investigated the effects of docetaxel, vinorelbine, and radiation on human breast fibroblasts and its modulation by melatonin. Docetaxel or vinorelbine inhibits proliferation and stimulates the differentiation of breast preadipocytes, by increasing C/EBPα and PPARγ expression and by downregulating tumor necrosis factor α (TNFα), interleukin 6 (IL-6), and IL-11 expression. Radiation inhibits both proliferation and differentiation through the downregulation of C/EBPα and PPARγ and by stimulating TNFα 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 effect of docetaxel and vinorelbine on differentiation and their inhibitory effects on aromatase activity and expression, by increasing the stimulatory effect on C/EBPα and PPARγ expression and the downregulation of antiadipogenic cytokines and COX expression. Melatonin also counteracts the inhibitory effect of radiation on differentiation of preadipocytes, by increasing C/EBPα and PPARγ expression and by decreasing TNFα expression. Melatonin also potentiates the inhibitory effect 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 effects induced by chemotherapeutic drugs or radiation on preadipocytes, which makes it a promising adjuvant for chemotherapy and radiotherapy sensibilization.
Highlights
The growth of malignant cells is conditioned by tumor microenvironment
It is known that malignant epithelial cells secrete antiadipogenic cytokines, such as TNF-α, IL-11, and Interleukin 6 (IL-6) that inhibit the differentiation of fibroblasts near the tumor into mature adipocytes and stimulate aromatase expression in these undifferentiated adipose fibroblasts [4]
Only melatonin 1 mM potentiated the inhibitory effect on cell proliferation and the stimulatory effect of docetaxel and vinorelbine on differentiation of breast preadipocytes
Summary
The growth of malignant cells is conditioned by tumor microenvironment. Normal cells that are close to the tumor cells provide them a structural support, but they are an active component in tumor evolution. It is known that malignant epithelial cells secrete antiadipogenic cytokines, such as TNF-α, IL-11, and IL-6 that inhibit the differentiation of fibroblasts near the tumor into mature adipocytes and stimulate aromatase expression in these undifferentiated adipose fibroblasts [4]. This blockage caused by the tumor cells in adipocyte differentiation is mediated by the inhibition of expression of the two main adipogenic transcription factors CCAAT/enhancer-binding protein (C/EBP)α and peroxisome proliferator-activated receptor (PPARγ) [4]. We investigated the effects of ionizing radiation or chemotherapeutics, like docetaxel or vinorelbine, no longer on tumor cells but on normal cells, human mammary fibroblasts, a kind of cell crucial in tumor microenvironment, and its modulation by melatonin
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