Dieckol, isolated from the edible brown algae Ecklonia cava, induces apoptosis of ovarian cancer cells and inhibits tumor xenograft growth
- 773 Downloads
Ecklonia cava is an abundant brown alga and has been reported to possess various bioactive compounds having anti-inflammatory effect. However, the anticancer effects of dieckol, a major active compound in E. cava, are poorly understood. In the present study, we investigated the anti-tumor activity of dieckol and its molecular mechanism in ovarian cancer cells and in a xenograft mouse model .
MTT assay, PI staining, and PI and Annexin double staining were performed to study cell cytotoxicity, cell cycle distribution, and apoptosis. We also investigated reactive oxygen species (ROS) production and protein expression using flow cytometry and Western blot analysis, respectively. Anti-tumor effects of dieckol were evaluated in SKOV3 tumor xenograft model.
We found that the E. cava extract and its phlorotannins have cytotoxic effects on A2780 and SKOV3 ovarian cancer cells. Dieckol induced the apoptosis of SKOV3 cells and suppressed tumor growth without any significant adverse effect in the SKOV3-bearing mouse model. Dieckol triggered the activation of caspase-8, caspase-9, and caspase-3, and pretreatment with caspase inhibitors neutralized the pro-apoptotic activity of dieckol. Furthermore, treatment with dieckol caused mitochondrial dysfunction and suppressed the levels of anti-apoptotic proteins. We further demonstrated that dieckol induced an increase in intracellular ROS, and the antioxidant N-acetyl-l-cysteine (NAC) significantly reversed the caspase activation, cytochrome c release, Bcl-2 downregulation, and apoptosis that were caused by dieckol. Moreover, dieckol inhibited the activity of AKT and p38, and overexpression of AKT and p38, at least in part, reversed dieckol-induced apoptosis in SKOV3 cells.
These data suggest that dieckol suppresses ovarian cancer cell growth by inducing caspase-dependent apoptosis via ROS production and the regulation of AKT and p38 signaling.
KeywordsApoptosis Ecklonia cava Dieckol Ovarian cancer Reactive oxygen species Tumor xenograft model
This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant (to JHC) funded by the Korea government (MEST) (2012R1A1A2039648 and 2010-0004306).
Conflict of interest
The authors have declared no conflict of interest.
- Gao LJ, Gu PQ, Zhao W, Ding WY, Zhao XQ, Guo SY, Zhong TY (2013) The role of globular heads of the C1q receptor in HPV 16 E2-induced human cervical squamous carcinoma cell apoptosis is associated with p38 MAPK/JNK activation. J Transl Med 11:118. doi: 10.1186/1479-5876-11-118 PubMedCentralPubMedCrossRefGoogle Scholar
- Onyango IG, Bennett JP Jr, Tuttle JB (2005) Endogenous oxidative stress in sporadic Alzheimer’s disease neuronal cybrids reduces viability by increasing apoptosis through pro-death signaling pathways and is mimicked by oxidant exposure of control cybrids. Neurobiol Dis 19:312–322. doi: 10.1016/j.nbd.2005.01.026 PubMedCrossRefGoogle Scholar
- Park SJ, Kim YT, Jeon YJ (2012) Antioxidant dieckol downregulates the Rac1/ROS signaling pathway and inhibits Wiskott-Aldrich syndrome protein (WASP)-family verprolin-homologous protein 2 (WAVE2)-mediated invasive migration of B16 mouse melanoma cells. Mol Cells 33:363–369. doi: 10.1007/s10059-012-2285-2 PubMedCentralPubMedCrossRefGoogle Scholar
- Sarafraz-Yazdi E, Pincus MR, Michl J (2013) Tumor-targeting peptides and small molecules as anti-cancer agents to overcome drug resistance. Curr Med ChemGoogle Scholar
- Yang YI, Shin HC, Kim SH, Park WY, Lee KT, Choi JH (2012) 6,6′-Bieckol, isolated from marine alga Ecklonia cava, suppressed LPS-induced nitric oxide and PGE(2) production and inflammatory cytokine expression in macrophages: the inhibition of NFkappaB. Int Immunopharmacol 12:510–517. doi: 10.1016/j.intimp.2012.01.005 PubMedCrossRefGoogle Scholar
- Zanotto-Filho A, Delgado-Canedo A, Schroder R, Becker M, Klamt F, Moreira JC (2010) The pharmacological NFkappaB inhibitors BAY117082 and MG132 induce cell arrest and apoptosis in leukemia cells through ROS-mitochondria pathway activation. Cancer Lett 288:192–203. doi: 10.1016/j.canlet.2009.06.038 PubMedCrossRefGoogle Scholar
- Zhao H, Kalivendi S, Zhang H, Joseph J, Nithipatikom K, Vasquez-Vivar J, Kalyanaraman B (2003) Superoxide reacts with hydroethidine but forms a fluorescent product that is distinctly different from ethidium: potential implications in intracellular fluorescence detection of superoxide. Free Radic Biol Med 34:1359–1368PubMedCrossRefGoogle Scholar