Regulation of Inflammation by the NF-κB Pathway in Ovarian Cancer Stem Cells

Department of Obstetrics Gynecology and Reproductive Sciences, Yale University, New Haven, CT 06520, USA.
American Journal Of Reproductive Immunology (Impact Factor: 2.44). 04/2011; 65(4):438-47. DOI: 10.1111/j.1600-0897.2010.00914.x
Source: PubMed


The NFκB pathway is a major source of pro-inflammatory cytokines, which may contribute to cancer chemoresistance. We showed that constitutive NFκB activity is characteristic of the ovarian cancer stem cells (OCSCs). The aim of this study is to determine whether the inhibition of NFκB by Eriocalyxin B (EriB) in the OCSCs may induce cell death in otherwise chemoresistant cells.
OCSCs and mature ovarian cancer cells (mOCCs) were treated with increasing concentrations of EriB. Cell viability was measured using the Celltiter 96 assay, and caspase activity was quantified using Caspase-Glo™ assay. Cytokine levels were quantified using xMAP technology.
EriB decreased the percent of viable cells in all cultures tested with GI(50) of 0.5-1 μm after 48 hrs of treatment. The intracellular changes associated with EriB-induced cell death are: (i) inhibition of NF-κB activity; (ii) decreased cytokine production; (iii) activation of caspases; and (iv) down-regulation of XIAP. In addition, EriB is able to sensitize OCSCs to TNFα and FasL-mediated cell death.
Inhibition of the NFκB pathway induces cell death in the OCSCs. Because the OCSCs may represent the source of recurrence and chemoresistance, the use of NFκB inhibitors like EriB may prevent recurrence in patients with ovarian cancer.


Available from: Gil Mor, Jan 19, 2015
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    • "Retinoids, in co-administration with cis-platinum, affect ovarian CSCs, whereas carboplatinum alone is not active (Whitworth et al., 2012). Ericalyxin B, a diterpenoid isolated from Isodon eriocalyx displaying antitumor effects via multiple pathways, and 3-Bromopiruvate target ovarian CSCs inducing cell death (Leizer et al., 2011; Wintzell et al., 2012). Dactinomycin and Plicamycin, two FDA-approved CSCs-inhibitory compounds, are used in the treatment of several cancers including gestational trophoblastic neoplasia, Wilms' tumor, testicular cancer and hypercalcemia associated with advanced malignancy (Kennedy, 1970; Perlia et al., 1970; Lewis et al., 1972; Frei, 1974; Fraschini et al., 2005; Lee et al., 2006). "
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    Frontiers in Pharmacology 07/2014; 5:163. DOI:10.3389/fphar.2014.00163 · 3.80 Impact Factor
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    • "The results of flow cytometric analysis showed that rates of apoptosis were 17.55 ± 2.13% and 24.94 ± 2.53% in the cells treated with 3 and 5 μM of EriB respectively for 24 h as compared to 5.88 ± 1.02% in the control cells (Figure 4). EriB -induced apoptosis in T24 cells was consistent with previously reported studies in ovarian cancer (Leizer et al., 2010), pancreatic adenocarcinoma (Li et al., 2012) and leukemia (Wang et al., 2007; Zhang et al., 2010). "
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    • "Constitutive activation of NF-κB and other pro-inflammatory signals in CD44+ ovarian CSCs appeared to correlate with chemoresistance to paclitaxel and carboplatin [89]. Inhibition of NF-κB by Eriocalyxin B induced cell death in chemoresistant CD44+ ovarian CSCs [90]. In breast CSCs, treatment with disulfiram and copper can inhibit consitutively active NF-κB while sensitizing these cells to paclitaxel [91]. "
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