Inhibition of Aurora Kinase A Synergistically Enhances Cytotoxicity in Ovarian Clear Cell Carcinoma Cell Lines Induced by Cisplatin

Chiba, Yohei; Sato, Seiya; Itamochi, Hiroaki; Yoshino, Naoto; Fukagawa, Daisuke; Kawamura, Hideki; Suga, Yasuko; Kojima-Chiba, Atsumi; Muraki, Yasushi; Sugai, Tamotsu; Sugiyama, Toru

doi:10.1097/igc.0000000000001081

Cited by 12 publications

(9 citation statements)

References 28 publications

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“…In addition, AURKA expression predicts platinum resistance in patients with high-grade serous ovarian carcinoma (Mignogna et al, 2016). Inhibiting AURKA by inhibitor ENMD-2076 enhances the cytotoxic effect of cisplatin in ovarian cancer (Chiba et al, 2017;Diamond et al, 2018). Our result is consistent with the effect of AURKA inhibitor on cisplatin therapy reported before (Chiba et al, 2017) and makes us more confident about the potential of emodin to use as an AURKA inhibitor in ovarian cancer therapy.…”

Section: Emodin On Aurka Activity and Ovarian Cancer Cisplatin Treatmentsupporting

confidence: 87%

Natural anthraquinone compound emodin as a novel inhibitor of aurora A kinase: A pilot study

Chu

Chen

et al. 2021

Chem Biol Drug Des

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Ovarian cancer is the seventh most commonly diagnosed cancer disease in women world worldwide and leads to 152,000 cancer-specific deaths annually (Reid et al., 2017).The five-year relative survival is about 45%. Standard treatment consists of tumor excision (removing tumor bigger than 1 mm) followed by chemotherapy (Arora et al., 2018). However, the response rate is still too low in some patients. In addition, the remaining problem with chemotherapies is

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Section: Emodin On Aurka Activity and Ovarian Cancer Cisplatin Treatmentsupporting

confidence: 87%

Natural anthraquinone compound emodin as a novel inhibitor of aurora A kinase: A pilot study

Chu

Chen

et al. 2021

Chem Biol Drug Des

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“…Aurora-A is an oncogene in mammary epithelium and gland (11, 12), whereas it functions as a tumor suppressor in neural stem cells (13), so Aurora-A functions differ depending on the cell type. Aurora-A has been reported in the gynecologic cancers, such as breast cancer (18), ovarian cancer (20, 24), and EC (22), but the underlying molecular mechanism of Aurora-A-mediated chemoresistance in EC is unclear. In the present study, we revealed that both of mRNA and protein up-regulation of Aurora-A frequently occur in EC and contribute to a poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…Increasing evidences have shown that overexpression of Aurora-A is associated with chemoresistance (14–19). Recent reports showed that Aurora-A is correlated with the resistance to carboplatin/Cisplatin and indicates a poor prognosis (20, 21). Aurora-A has been noted to be a novel therapeutic target for the gynecological malignancies, however, only a few reports have described a role for Aurora-A in EC.…”

Section: Introductionmentioning

confidence: 99%

Aurora-A Induces Chemoresistance Through Activation of the AKT/mTOR Pathway in Endometrial Cancer

Cheng

et al. 2019

Front. Oncol.

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Endometrial cancer (EC) is the most common gynecological tumor all over the world, and advanced/metastatic EC remains a malignancy with poor survival outcome due to highly resistant to conventional chemotherapeutic treatment. Here, we report that Aurora-A, a serine-threonine kinase, plays a vital role in chemoresistance of EC. Aurora-A is overexpressed in EC tissues, compared with normal endometrium and Aurora-A expression is associated with decreased overall survival. Overexpression of Aurora-A in EC cell lines (Ishikawa and HEC-1B cells) promotes cell proliferation and induced paclitaxel- and cisplatin-resistance. Furthermore, Aurora-A activating AKT-mTOR pathway further induces chemoresistance in vitro , consistent with a positive correlation between Aurora-A and phosphorylated AKT/4E-BP1 expression in EC tissues. In summary, our study provides the strong evidence that Aurora-A controls the sensitivity of EC cell lines to chemotherapy via AKT/mTOR pathway, indicating that pharmacologic intervention of Aurora-A and AKT/mTOR in combination with chemotherapy may be considered for the targeted therapy against EC with overexpression of Aurora-A.

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“…This overexpression is also correlated with decreased survival in women with early stage disease [20,21]. In advanced OCCC, increased Aurora-A expression was associated with worse overall survival [22]. A recent study had shown that overexpression of Aurora Kinase A was significantly associated with chemoresistance in OCCC, suggesting that targeted at Aurora Kinase might provide a promising therapeutic option [23].…”

Section: Introductionmentioning

confidence: 99%

A Clinical and Molecular Phase II Trial of Oral ENMD-2076 in Ovarian Clear Cell Carcinoma (OCCC): A Study of the Princess Margaret Phase II Consortium

Lheureux

Tinker

Clarke

et al. 2018

Clinical Cancer Research

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Patients with recurrent ovarian clear cell carcinoma (OCCC) have limited effective options due to chemoresistance. A phase II study was designed to assess the activity of ENMD-2076, an oral multitarget kinase selective against Aurora A and VEGFR. This multicenter phase II study included patients with recurrent OCCC who received prior platinum-based chemotherapy. Primary endpoints were objective response and 6-month progression-free survival (PFS) rates. Correlative analyses include ARID1A and PTEN expression by IHC and gene sequencing with a targeted custom capture next-generation sequencing panel. Forty patients were enrolled with a median age of 54, of which 38 patients were evaluable. ENMD-2076 was well tolerated with main related grade 3 toxicities being hypertension (28%), proteinuria (10%), and diarrhea (10%). Best response was partial response for 3 patients (1 unconfirmed) and stable disease for 26 patients. The overall 6-month PFS rate was 22% and differed according to ARID1A expression (ARIDIA vs. ARID1A; 33% vs. 12%, = 0.023). PTEN-positive expression was observed in 20 of 36 patients, and there was no correlation with outcome. Median PFS in patients with wild-type versus -mutated group was 5 versus 3.7 months ( = 0.049). Molecular profiling showed variants in (27%), (26%), and (7%). The patient with the longest treatment duration (22 months) was wild-type, diploid PTEN with putative biallelic inactivation of Single-agent ENMD-2076 did not meet the preset bar for efficacy. Loss of ARID1A correlated with better PFS on ENMD-2076 and warrants further investigation as a potential predictive biomarker.

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Inhibition of Aurora Kinase A Synergistically Enhances Cytotoxicity in Ovarian Clear Cell Carcinoma Cell Lines Induced by Cisplatin

Abstract: Aurora-A is a promising biomarker that is predictive of patient outcomes and a potential target for OCCC. The results suggested that chemotherapy, including ENMD-2076 in combination with cisplatin, is a potential treatment modality for patients with OCCC.

Cited by 12 publications

References 28 publications

Natural anthraquinone compound emodin as a novel inhibitor of aurora A kinase: A pilot study

Natural anthraquinone compound emodin as a novel inhibitor of aurora A kinase: A pilot study

Aurora-A Induces Chemoresistance Through Activation of the AKT/mTOR Pathway in Endometrial Cancer

A Clinical and Molecular Phase II Trial of Oral ENMD-2076 in Ovarian Clear Cell Carcinoma (OCCC): A Study of the Princess Margaret Phase II Consortium

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