Abstract
Oleanane triterpenoids are broad-spectrum antiproliferative and proapoptotic agents. In this study, we investigated whether reactive oxygen species (ROS) play a role in the antitumor activity of methyl-2-cyano-3, 12-dioxooleana- 1, 9(11)-dien-28-oate (CDDO-Me) in OVCAR-5 and MDAH 2774 ovarian cancer cells. Treatment with CDDO-Me caused the generation of ROS (H2O2) and pre-treatment with Nacetylcysteine (NAC) prevented the generation of ROS. NAC also blocked the inhibition of cell proliferation by CDDO-Me. Likewise, NAC prevented the CDDO-Me-caused binding of fluorescein isothiocyanate (FITC)-tagged annexin V, cleavage of poly ADP-ribose polymerase-1 (PARP-1), procaspases-3, -8 and -9 and loss of mitochondrial membrane potential. CDDO-Me inhibited the expression of prosurvival phospho- AKT (p-AKT), phospho-mammalian target of rapamycin (p-mTOR) and nuclear factor-kappa B (NF-κB) (p65) signaling molecules and NF-κB-regulated antiapoptotic B-cell lymphoma-2 (BCL-2), B-cell lymphoma-extra large (BCL-xL), cellular inhibitor of apoptosis protein 1(c-IAP1) and survivin, but pre-treatment with NAC blocked the down-modulation of these signaling and antiapoptotic proteins by CDDO-Me. Together, these results indicate the pivotal role ROS play in the antiproliferative- and apoptosis-inducing activity of CDDO-Me in ovarian cancer cells; however, the role of ROS in the down-regulation of prosurvival AKT, mTOR, NF-κB and antiapoptotic BCL-2, BCL-xL, c-IAP1 and survivin warrants further investigation.
Original language | English (US) |
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Pages (from-to) | 215-222 |
Number of pages | 8 |
Journal | Anticancer research |
Volume | 33 |
Issue number | 1 |
State | Published - Jan 2013 |
Externally published | Yes |
Keywords
- AKT
- Apoptosis
- CDDO-Me
- MTOR
- NF-κB
- Ovarian cancer
- ROS
ASJC Scopus subject areas
- Oncology
- Cancer Research