Targeting multiple signaling pathways in ovarian cancer by diindolylmethane

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2012-05

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Abstract

Ovarian cancer is the leading gynecologic malignancy with more than 22,000 new cases and 15,000 deaths estimated each year. It is usually detected in late stages with poor prognosis due to lack of sufficiently accurate screening tests. Epidemiological studies indicated an inverse relationship between consumption of cruciferous vegetables and incidence of ovarian cancer. Hence, in our studies we tested the anti-cancer effects of 3, 3’-diindolylmethane (DIM), a compound present in cruciferous vegetables against ovarian cancer. Our cytotoxicity results showed that DIM reduces the proliferation of SKOV3, OVCAR3 and TOV-21G ovarian cancer cells in a concentration and time dependent manner. The growth suppressive effects of DIM were mediated by G2/M cells cycle arrest that was regulated by the activation of Chk2 in response to ROS mediated DNA damage. Our results also showed that DIM-induced apoptosis in six different ovarian cancer cell lines was mediated by the inhibition of EGFR-JAK2-STAT3 axis. Stimulation with EGF, IL-3, IL-6 or ectopic expression of STAT3 by transfection remarkably blocked DIM- mediated apoptosis in SKOV3 ovarian cancer cells. Our results demonstrated that DIM blocks angiogenesis and invasion by inhibiting VEGF and HIF-1α in our model. DIM treatment also led to induction of anoikis via suppression of hedgehog signaling transcription factor Gli1. DIM treatment also led to ER stress and AMPK mediated autophagy. Oral administration of DIM significantly suppressed the growth of ovarian tumors in athymic nude mice. Our interesting results also demonstrated that DIM potentiates the effect of cisplatin in vitro and in vivo. Taken together, our pre-clinical studies demonstrate that DIM has activity against ovarian cancer and hence it should be further investigated in clinic to exploit its therapeutic potential.

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Keywords

Ovaries--Cancer, Apoptosis

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