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Gynecol Oncol. 2011 Dec;123(3):588-96. doi: 10.1016/j.ygyno.2011.08.031. Epub 2011 Sep 25.

Costunolide induces apoptosis in platinum-resistant human ovarian cancer cells by generating reactive oxygen species.

Author information

1
Department of Life & Nanopharmaceutical Science, Kyung Hee University, Seoul, Republic of Korea.

Abstract

OBJECTIVE:

The acquired resistance to platinum-based drugs has become an obstacle in the management of ovarian cancer. We investigated the apoptosis-inducing effect of costunolide, a natural sesquiterpene lactone, in platinum-resistant human ovarian cancer cells, along with the molecular mechanism of action.

METHODS:

Costunolide and cisplatin were examined in platinum-resistant human ovarian cancer cells. MTT assay for cell viability, PI staining for cell cycle profiling, and Annexin V assay for apoptosis analysis. ROS production and protein expression was assessed by H(2)DCFDA staining and Western blotting, respectively. Combination effect was determined using the Combination Index (CI) method.

RESULTS:

It was found that costunolide is more potent than cisplatin in inhibiting cell growth in three platinum-resistant ovarian cancer cell lines (MPSC1(PT), A2780(PT), and SKOV3(PT)). Costunolide induced apoptosis of platinum-resistant cells in a time- and dose-dependent manner and suppressed tumor growth in SKOV3(PT)-bearing mouse model. In addition, costunolide triggered the activation of caspase-3, -8, and -9. Pretreatment with caspase inhibitors neutralized the pro-apoptotic activity of costunolide. We further demonstrated that costunolide induced a significant increase in intracellular reactive oxygen species (ROS). Additionally, the antioxidant N-acetyl-L-cysteine (NAC) significantly attenuated the costunolide-induced production of ROS, activation of caspases, down-regulation of Bcl-2, and apoptosis in platinum-resistant ovarian cancer cells. Moreover, costunolide synergized with cisplatin to induce cell death in platinum-resistant ovarian cancer cells.

CONCLUSIONS:

Taken together, these data suggest that costunolide, alone or in combination with cisplatin, may be of therapeutic potential in platinum-resistant ovarian cancer.

PMID:
21945308
DOI:
10.1016/j.ygyno.2011.08.031
[Indexed for MEDLINE]

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