Amelioration of Dalton’s lymphoma–induced angiogenesis by melatonin

Abstract

For tumor to grow beyond 1-2 mm size, tumor recruits new blood vessels referred as angiogenesis; therefore, targeting angiogenesis can be a promising strategy to suppress cancer progression. In this study, in order to develop a good angiogenesis model, we investigated effect of Dalton's lymphoma on angiogenesis and further monitored the role of melatonin on regulation of angiogenesis. To evaluate angiogenesis, endothelial cells were isolated from main thoracic aorta and cultured in vitro in the presence or absence of Dalton's lymphoma supplemented with or without melatonin to monitor their role on its proliferation and migration, a hallmark of angiogenesis. Chick chorioallantoic membrane as well as mice mesentery which allows in vivo studies of tumor angiogenesis and testing of anti-angiogenic molecules was used to validate the in vitro analysis. To further extend our understanding about the regulation of the angiogenesis, we evaluated expression of tissue inhibitor of metalloproteinases 3, vascular endothelial growth factor, vascular endothelial growth factor receptor, and fibroblast growth factor in Dalton's lymphoma cells and mesentery by semiquantitative and quantitative reverse transcription polymerase chain reaction analysis. Dalton's lymphoma ascites induced significant increase in endothelial cell proliferation, migration, and sprouting of the tertiary branching in chorioallantoic membrane and mesentery of Dalton's lymphoma-bearing mice, whereas melatonin treatment led to their inhibition in a dose-dependent manner. Semiquantitative and quantitative reverse transcription polymerase chain reaction analysis of melatonin-treated Dalton's lymphoma cells and mesentery tissue clearly demonstrated restoration of angiogenesis-related genes tissue inhibitor of metalloproteinases 3 and reduction of vascular endothelial growth factor, vascular endothelial growth factor receptor, and fibroblast growth factor messenger RNA expression. Taken together, our results strongly demonstrate that Dalton's lymphoma provides pro-angiogenic environment leading to significant increase in angiogenesis, and further melatonin treatment reduced the Dalton's lymphoma ascites-induced angiogenesis implying that Dalton's lymphoma can serve as a very good model to study angiogenesis as well as for screening of drugs that can target angiogenesis.

Usefulness of melatonin as complementary to chemotherapeutic agents at different stages of the angiogenic process

“…Melatonin, alone or in combination with vinorelbine, also increased TIMP3 expression, an inhibitor of angiogenesis that limits vessel density close to tumors and reduces tumor growth 67 . Recently, it has been described that melatonin reduces Dalton's lymphoma-induced angiogenesis by increasing TIMP3 expression 68 .…”

Melatonin as an Adjuvant to Antiangiogenic Cancer Treatments

“…Melatonin inhibited the proliferation, migration, and sprouting of the tertiary branching in chorioallantoic membrane and mesentery of Dalton's lymphomabearing mice. In addition, the indolamine was capable to restore anti-angiogenic related genes, such as tissue inhibitor of metalloproteases 3 (TIMP-3), reducing, at the same time, the expression of VEGF, VEGFR, and FGF [86]. In glioblastoma stem-like cells, melatonin inhibited the pro-angiogenic EZH2-NOTCHI signaling pathway [87].…”

Melatonin and cancer: From the promotion of genomic stability to use in cancer treatment

“…were defined for Dalton lymphoma, renal adenocarcinoma, colon cancer cells, and ovarian carcinoma cells (K. J. Kim et al, 2013;Kumari, Rawat, Kumari, & Shrivastava, 2017;Park et al, 2010;Zonta et al, 2017). In the human gastric cancer cells it has been shown that melatonin beside to VEGF and HIF-1 can reduce angiogenesis by suppression of nuclear receptor RZR/RORγ (R.-X.…”