Ameliorative effects of luteolin against endometriosis progression in vitro and in vivo

J Nutr Biochem. 2019 May;67:161-172. doi: 10.1016/j.jnutbio.2019.02.006. Epub 2019 Mar 3.

Abstract

Endometriosis is a common gynecological disease in reproductive-aged women. Generally, accumulation of backflow and debris of endometrial tissue develops into a lesion outside of the endometrium, inducing severe pelvic pain and infertility in some patients. Hormone therapy and surgery are the main treatments available, but various therapeutic phytochemicals are being reviewed in animal studies or clinical trials for endometriosis patients nowadays. However, the therapeutic effects of luteolin in human endometriosis have not been studied well. Here, we demonstrate that luteolin exerts antiproliferative and apoptotic effects in human VK2/E6E7 and End1/E6E7 and in an animal endometriosis model. Luteolin inhibits cell proliferation through cell cycle arrest and induces apoptosis through DNA fragmentation in VK2/E6E7 and End1/E6E7 cells. Cytosolic calcium levels, ROS production and lipid peroxidation also increased dose-dependently (0, 5, 10 and 20 μM) in the treatment with luteolin. In VK2/E6E7 and End1/E6E7 cells, luteolin decreased ERK1/2, JNK and PI3K/AKT signal proteins while activating P38. In addition, intraperitoneal injection of luteolin in the endometriosis mouse model reduced lesion size compared to vehicle-injected mice. Ccne1, Cdk2 and Cdk4 were significantly down-regulated in the autoimplanted endometriosis lesions of mice intraperitoneally injected with luteolin. Knockdown of CCNE1 mRNA in VK2/E6E7 and End1/E6E7 cells decreased cell viability through inhibition of G0/G1 phase progression and increased apoptosis. Together, our results imply that luteolin suppresses endometriosis development by regulation of the PI3K/AKT and MAPK signal proteins as well as the expression of CCNE1 in vitro and in vivo.

Keywords: Anti-proliferation; CCNE1; Cell cycle arrest; Endometriosis; Luteolin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Checkpoints / genetics
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cyclin E / genetics
  • Cyclin E / metabolism
  • Disease Models, Animal
  • Endometriosis / drug therapy*
  • Endometriosis / pathology*
  • Female
  • Humans
  • Luteolin / pharmacology*
  • Mice, Inbred C57BL
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reactive Oxygen Species / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • CCNE1 protein, human
  • Cyclin E
  • Oncogene Proteins
  • Reactive Oxygen Species
  • Proto-Oncogene Proteins c-akt
  • p38 Mitogen-Activated Protein Kinases
  • Luteolin
  • Calcium