Molecular Mechanism of Daurinol, an Analog of Etoposide, for Cancer Chemopreventive Effects

Molecular Mechanism of Daurinol, an Analog of Etoposide, for Cancer Chemopreventive Effects
강경수오승현윤지호조은혜강주희Dulamjav BatsurenJigjidsuren Tunsag박광화노주원
Daurinol; Cancer; Chemoprevention; Etoposide
Issue Date
Indonetian Society of Cancer Chemoprevention
Daurinol is an arylnaphthalene lignan isolated from Mongolian medicinal plant, Haplophyllum dauricum. We found that daurinol inhibited cell proliferation of HCT116 human colorectal adenocarcinoma cells in a dose- and time- dependent manner, and anti-proliferative effect of daurinol was due to cell cycle arrest at S phase and apoptosis. In this study, we further investigated the molecular mechanisms of cancer suppressing activity of daurinol. Thus, we hypothesized that daurinol inhibits DNA synthesis and thereby it triggers a stress signaling involving DNA insufficiency. Here, we comprehensively compared the mechanistic differences between daurinol and etoposide because they have similar chemical structures. Etoposide, a topoisomerase II poison, is known to attenuate cancer cell proliferation via the inhibition of DNA synthesis. Etoposide treatment induces G2/M arrest, severe DNA damage, and the formation of giant nuclei in HCT116 cells. We hypothesized that the induction of DNA damage and nuclear enlargement due to abnormal chromosomal conditions could give rise to genomic instability in both tumor cells and in actively dividing normal cells, resulting in the toxic side effects of etoposide. We found that daurinol is a catalytic inhibitor of human topoisomerase IIα, and it induces S-phase arrest through the enhanced expression of cyclins E and A by activation of the ATM/Chk/Cdc25A pathway in HCT116 cells. However, daurinol treatment did not cause DNA damage or nuclear enlargement in vitro. Finally, we confirmed the in vivo antitumor effects and side effects of daurinol and etoposide in nude mice xenograft models. Daurinol displayed potent antitumor effects without any significant loss of body weight or changes in hematological parameters, whereas etoposide treatment led to decreased body weight and white blood cell, red blood cell, and platelet counts.
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