Potential new chemotherapy strategy for human ovarian carcinoma with a novel KSP inhibitor

Takenaga, Mitsuko; Yamamoto, Yoshiya; Takeuchi, Tomoki; Ohta, Yuki; Tokura, Yukie; Hamaguchi, Akemi; Asai, Daisuke; Nakashima, Hideki; Oishi, Shinya; Fujii, Nobutaka

doi:10.1016/j.bbrc.2015.05.029

Cited by 7 publications

(6 citation statements)

References 28 publications

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“…Inhibition of kinesin spindle proteins have been found to be effective in attenuating the progression of ovarian cancer. 56 Shi et al showed that KIF11 was up-regulated in ovarian cancer tissues and KIF11 overexpression eliminated the suppression of ovarian cancer cell migration by death receptor 6 knockdown. 57 Recent studies found that KIF11 was associated with the prognosis of patients with ovarian cancer by using bioinformatics analysis.…”

Section: Discussionmentioning

confidence: 99%

Identification of the Hub Genes Associated with the Prognosis of Ovarian Cancer Patients via Integrated Bioinformatics Analysis and Experimental Validation

Zhao

Liu

et al. 2021

CMAR

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Background This study aimed to identify the hub genes associated with prognosis of patients with ovarian cancer by using integrated bioinformatics analysis and experimental validation. Methods Four microarray datasets (GSE12470, GSE14407, GSE18521 and GSE46169) were analyzed by the GEO2R tool to screen common differentially expressed genes (DEGs). Gene Ontology, the Kyoto Encyclopedia of Genes and Genomes, the (KEGG) pathway and Reactome pathway enrichment analysis, protein–protein interaction (PPI) construction, and the identification of hub genes were performed. Furthermore, we performed the survival and expression analysis of the hub genes. In vitro functional assays were performed to assess the effects of hub genes on ovarian cancer cell proliferation, caspase-3/7 activity and invasion. Results A total of 89 common DEGs were identified among these four datasets. The KEGG and Reactome pathway results showed that the DEGs were mainly associated with cell cycle, mitotic and p53 signaling pathway. A total of 20 hub genes were identified from the PPI network by using sub-module analysis. The survival analysis revealed that high expression of six hub genes ( AURKA, BUB1B, CENPF, KIF11, KIF23 and TOP2A ) were significantly correlated with shorter overall survival and progression-free survival of patients with ovarian cancer. Furthermore, the expression of the six hub genes were validated by the GEPIA database and Human Protein Atlas, and functional studies revealed that knockdown of KIF11 and KIF23 suppressed the SKOV3 cell proliferation, increased caspase-3/7 activity and attenuated invasive potentials of SKOV3 cells. In addition, knockdown of KIF11 and KIF23 up-regulated E-cadherin mRNA expression but down-regulated N-cadherin and vimentin mRNA expression in SKOV3 cells. Conclusion Our results showed that six hub genes were up-regulated in ovarian cancer tissues and may predict poor prognosis of patients with ovarian cancer. KIF11 and KIF23 may play oncogenic roles in ovarian cancer cell progression via promoting ovarian cancer cell proliferation and invasion.

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Section: Discussionmentioning

confidence: 99%

Identification of the Hub Genes Associated with the Prognosis of Ovarian Cancer Patients via Integrated Bioinformatics Analysis and Experimental Validation

Zhao

Liu

et al. 2021

CMAR

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“…Furthermore, KPYB10602 suppressed tumor growth without apparent toxicity in the subcutaneous xenograft tumor model. In a previously reported study, mice treated with KPYB10602 did not exhibit significantly impaired in motor coordination 19) . KSP is responsible for centrosome separation, which is required for formation and maintenance of the bipolar spindle 8)18) .…”

Section: )6)7)mentioning

confidence: 69%

A Novel KSP Inhibitor, KPYB10602, Induces Mitotic Arrest and Cell Death in Breast Cancer Cells

Kojima-Tsuchiya

Ohta

Takenaga

et al. 2016

J St. Marianna Univ

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Purpose: Taxane-based combination chemotherapy remains the predominant treatment for breast cancer. However, taxane-related drug resistance and neurotoxicity have prompted us to develop substitute treatment strategies. Kinesin spindle protein (KSP), which is essential for formation of the bipolar mitotic spindle and cell cycle progression through mitosis, has been identified as an attractive target for cancer chemotherapy. We investigated, both in vitro and in vivo, the anti-cancer effect of KPYB10602, a novel KSP inhibitor, in breast cancer. Materials and Methods: Anti-proliferative activity of KPYB10602 in breast cancer cells was assessed by cell viability assay. The anti-cancer effect and inhibitory mechanism of KPYB10602 in breast cancer cells was further explored by immunofluorescence microscopy, flow cytometry, ELISA, and western blotting. In addition, the anti-tumor effect of KPYB10602 was evaluated in subcutaneous xenograft models. Results: KPYB10602 showed anti-cancer activity in breast cancer cells. The KPYB10602 treatment was shown to result in induction of mitotic arrest with monopolar spindle formation and then apoptotic cell death. This might occurred via a mitochondria-mediated pathway. KPYB10602 also effectively suppressed tumor growth in a subcutaneous xenograft model. Conclusion: KSP is a good target for breast cancer chemotherapy, and KPYB10602 has a potential as a novel anti-cancer agent for breast cancer.

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“…Furthermore, the anti-cancer activities of 8-bromo-7-methoxychrysin (BrMC), a novel chrysin analog, induces apoptosis of cisplatin-sensitive and resistant ovarian cancer cells accompanied with the upregulation of BIM (proapoptotic BH3-only) with inhibited expression of p-FOXO3a (a Forkhead box transcription factor important in regulation of cellular function) in cells, leading to apoptosis in human ovarian cancer cell line [107]. A carbazole-derivative KSP inhibitor, KPYB10602, which is the most potent of the KSP inhibitors tested in vitro, has in vivo anti-tumor activity in an A2780 human ovarian cancer xenograft model, enhancing the expression of BAX and slightly decreasing BCL2 leading to BAX/BCL2 ratio increased with ROS (reactive oxygen species) production via promotion of cytochrome c release [108]. Except for the traditional therapies, combination of paclitaxel and phytochemical piperine showed promising effect given the increase Bax/Bcl-2 ratio in human ovarian adenocarcinomas [109].…”

Section: Therapeutic Approach For Impaired Insulin and Androgen Pathway In Ovary And Endometriummentioning

confidence: 99%

BCL2 Family Genes Expression in Gynecological Diseases

Lasorella¹

2019

JGWH

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BCL2 family proteins are a very well-studied protein group for their critical role in cellular apoptosis. Apoptosis is involved in many biological phenomena and it is the basis of normal cellular homeostasis. It depends on a complex series of signals that are necessary for the homeostasis of our body. In this complex mechanism is involved a large family of oncogenes and tumor suppressor genes whose altered operation can lead to serious tissue disorders. Modifications of its complex processes have been recognized as responsible for different human pathologies including cancer, autoimmunity, neurodegenerative disorders and diabetes. Our review focuses on the normal functions and deregulation of BCL2 family genes in different gynecological pathologies: uterine congenital malformation, metabolic alterations (insulin-resistance and hyperandrogenemia), effect on ovarian follicles and endometrium proliferation. Certainly the connection between hormone alterations and interference with normal cell cycle are much investigated but further studies are necessary to better understand dysmetabolic pattern in which BCL2 members are involved in order to implement, where possible, a direct or indirect therapy aiming to restore the altered balance.

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Potential new chemotherapy strategy for human ovarian carcinoma with a novel KSP inhibitor

Cited by 7 publications

References 28 publications

Identification of the Hub Genes Associated with the Prognosis of Ovarian Cancer Patients via Integrated Bioinformatics Analysis and Experimental Validation

Identification of the Hub Genes Associated with the Prognosis of Ovarian Cancer Patients via Integrated Bioinformatics Analysis and Experimental Validation

A Novel KSP Inhibitor, KPYB10602, Induces Mitotic Arrest and Cell Death in Breast Cancer Cells

BCL2 Family Genes Expression in Gynecological Diseases

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