BMC Med：二吲哚甲烷对顺铂减毒增效 联用抗癌效果更佳

Prabodh K Kandala and Sanjay K Srivastava

Background
STAT-3 is activated in majority of ovarian tumors and confers resistance to cisplatin treatment in patients with ovarian cancer. We have reported previously that Diindolylmethane (DIM) inhibits the growth of ovarian cancer cells. However, the exact mechanism by which DIM induces growth suppressive effects was not yet understood and hence evaluated in this report.
Methods
Six human ovarian cancer cells and ovarian tumor xenograft animal model were used to study the effect of diindolylmethane alone or in combination of cisplatin.
Results
Diindolylmethane treatment induced apoptosis in all the six ovarian cancer cells. Phosphorylation of STAT3 at Tyr-705 and Ser-727 was reduced by DIM in a concentration-dependent manner. In addition, diindolylmethane treatment inhibited nuclear translocation, DNA binding, and transcriptional activity of STAT3. IL-6-induced phosphorylation of STAT3 at Tyr-705 was significantly blocked by DIM. Overexpression of STAT3 by gene transfection blocked DIM-induced apoptosis. In addition, diindolylmethane treatment reduced the levels of IL-6 in ovarian cancer cells and in the tumors. Diindolylmethane treatment also inhibited cell invasion and angiogenesis by suppressing HIF-1alpha and VEGF. Importantly, diindolylmethane treatment potentiated the effects of cisplatin in SKOV-3 cells by targeting STAT3. Oral administration of 3 mg diindolylmethane per day and subsequent administration of cisplatin substantially inhibited in vivo tumor growth. Western blotting analysis of tumor lysates indicated increased apoptosis and reduced STAT3 activation.
Conclusion
These findings provide a rationale for further clinical investigation of diindolylmethane alone or in combination for chemoprevention and/or chemotherapy of ovarian cancer.