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Sequential combination of cisplatin with eugenol targets ovarian cancer stem cells through the Notch-Hes1 signalling pathway.

ABSTRACT: BACKGROUND:Ovarian carcinomas are the deadliest gynecological malignancies owing to their high rate of recurrence and high resistance to platinum-based chemotherapy. Recent studies have shown platinum-dependent enrichment of ovarian tumors with side population as well as cancer stem cells, which are highly resistant to the treatment. To overcome this treatment-limiting factor, we sought to combine cisplatin with eugenol, a natural substance known to have anti-cancer effects. METHODS:The efficiency of combining cisplatin with eugenol was first tested in vitro on two ovarian cancer cell lines SKOV3 and OV2774 using the WST1 and the flow cytometry techniques. The effect of this combination on ovarian cancer stem cells was determined by the tumorsphere formation assay, while the implication of the Notch pathway was evaluated post-ectopic expression of the Hes1 gene. The resulting changes in the expression of several markers was assessed by immunoblotting, immunofluorescence as well as quantitative RT-PCR. Cell sorting was also used to isolate specific ovarian cancer sub-population of cells. Furthermore, tumor-bearing mouse models were utilized to prove the potential therapeutic value of the cisplatin/eugenol combination treatment in vivo. RESULTS:We have shown that adding eugenol to cisplatin-treated ovarian cancer cells synergistically inhibited their growth and survival through induction of apoptosis. Importantly, this sequential inhibition strongly reduced the proportion of side population cells and suppressed cisplatin-dependent enrichment in ovarian cancer stem cells. Additionally, while increase in the level of Hes1 promoted stemness and enhanced resistance to cisplatin, cisplatin/eugenol cotreatment inhibited the Notch-Hes1 pathway and strongly downregulated the drug resistance ABC transporter genes. These findings were confirmed in vivo by showing that cisplatin/eugenol cotherapy inhibited tumor growth in animals, reduced the proportion and self-renewal capacities of cancer stem cells and significantly improved disease-free survival of tumor-bearing animals compared with either therapy alone. CONCLUSIONS:These results indicate that cisplatin/eugenol sequential combination could be of great therapeutic value for ovarian cancer patients through targeting the Notch-Hes1 pathway and the consequent elimination of the resistant cancer stem cells.

SUBMITTER: Islam SS

PROVIDER: S-EPMC6716935 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Sequential combination of cisplatin with eugenol targets ovarian cancer stem cells through the Notch-Hes1 signalling pathway.

Islam Syed S SS Aboussekhra Abdelilah A

Journal of experimental & clinical cancer research : CR 20190830 1

<h4>Background</h4>Ovarian carcinomas are the deadliest gynecological malignancies owing to their high rate of recurrence and high resistance to platinum-based chemotherapy. Recent studies have shown platinum-dependent enrichment of ovarian tumors with side population as well as cancer stem cells, which are highly resistant to the treatment. To overcome this treatment-limiting factor, we sought to combine cisplatin with eugenol, a natural substance known to have anti-cancer effects.<h4>Methods</ ...[more]

PMID: 31470883

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Project description:Epithelial ovarian cancer (EOC) is the most lethal cancer among female genital tumours. Standard therapies, including postoperative chemotherapy, exhibit high proportions of recurrence and resistance. Novel therapeutic strategies are combined with chemotherapy. Emerging studies have demonstrated that nigericin, an H+, K+ and Pb2+ ionophore, exhibits promising anticancer activity in various types of malignancy, such as colorectal and epithelial ovarian cancer. Our previous study suggested that nigericin could regulate EOC cell proliferation, migration and invasion, and may be a novel chemotherapy candidate for EOC. However, to the best of our knowledge, the effects of combined therapy with cisplatin, and the associated underlying mechanisms, are not yet fully understood. The present study aimed to clarify the effects of combined chemical therapy with nigericin and cisplatin on EOC cells and to reveal its mechanism. Wound healing, Transwell, cell viability and colony formation assays were used to measure the migration, invasion and proliferation of EOC cells. Western blotting was used to detect protein expression. A slug overexpression lentivirus was used to create a slug overexpression model in SK-OV-3 cells. Small interfering RNA was used to knock down slug expression. Nigericin combined with cisplatin enhanced the inhibitory effects of cisplatin on the migration and colony formation of EOC cells. Nigericin also enhanced the inhibitory effects of cisplatin on the expression levels of MMP7, as well as the inhibitory effects of cisplatin on the expression levels of β-catenin and GSK-3β, indicating that nigericin and cisplatin regulated in the Wnt/β-catenin signalling pathway. When slug was knocked down, the effect of nigericin was weakened. Overexpression of slug could repress the inhibitory effect of nigericin on the Wnt/β-catenin signalling pathway. Furthermore, nigericin inhibited slug expression by enhancing its modification through small ubiquitin-like modifiers (SUMOs; referred to as SUMOylation). Overall, the present results demonstrated that nigericin combined with cisplatin might serve as a novel therapeutic strategy in patients with metastatic EOC because the combined therapy had higher effectiveness than single drug use. The underlying mechanism of combined therapy maybe the enhanced inhibitory effect of slug through its nigericin-induced SUMOylation.

Project description:BackgroundOvarian cancer has one of the highest mortality rates among all gynaecological malignancies, and increasing evidence suggests that lncRNAs are widely involved in the development of ovarian tumours. This study aimed to investigate the mechanism of the LNC00115/miR-7/ERK axis in the cisplatin resistance of ovarian cancer cells.MethodsThe expression of miR-7 and LNC00115 in ovarian cancer cell lines and tissues was detected by qRT-PCR. The ovarian cancer cell lines were constructed by overexpressing or knocking down the expression of LNC00115 or miR-7. CCK-8, transwell invasion, Western blot, immunohistochemistry, and luciferase reporter assays were carried out to identify the targets of LNC00115 and explore its roles and mechanisms in ovarian cancer. A nude mouse model was established, and the expression of LNC00115, miR-7 and ERK was detected. The changes in the tumours and body weights of the nude mice were measured.ResultsLNC00115 was upregulated in ovarian cancer tissues and cisplatin-resistant ovarian cancer cells. Moreover, LNC00115 promoted the cisplatin resistance, invasion and migration of ovarian cancer cells. LNC00115 was shown to directly target miR-7, and miR-7 was downregulated in ovarian cancer tissues and cisplatin-resistant ovarian cancer cells. miR-7 inhibited the cisplatin resistance, invasion and migration of ovarian cancer cells and directly targeted ERK. ERK was overexpressed in cisplatin-resistant ovarian cancer cells and ovarian cancer tissues. In animal experiments, overexpression of LNC00115 enhanced the cisplatin resistance of ovarian cancer cells, while miR-7 had the opposite effect. Mechanistically, LNC00115 sponged miR-7 to increase the expression of ERK, which in turn enhanced the cisplatin resistance of ovarian cancer.ConclusionOur data clarify the mechanism by which the LNC00115/miR-7/ERK axis promotes cisplatin resistance and provide a new clinical strategy for combating cisplatin resistance in ovarian cancer.

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Sequential combination of cisplatin with eugenol targets ovarian cancer stem cells through the Notch-Hes1 signalling pathway.

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Sequential combination of cisplatin with eugenol targets ovarian cancer stem cells through the Notch-Hes1 signalling pathway.

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