Aurora kinase inhibitor VE 465 synergistically enhances cytotoxicity of carboplatin in ovarian cancer cells through induction of apoptosis and downregulation of histone 3

Fu, Siqing; Li, Yanfang; Huang, Jie; Liu, Tao; Hong, Zihan; Chen, Aiping; Bast, Robert C.; Kavanagh, John J.; Gershenson, David M.; Sood, Anil K.; Hu, Wei

doi:10.4161/cbt.21045

Cited by 13 publications

(8 citation statements)

References 30 publications

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“…, 2007 ; Van Horn et al ., 2010 ). Either inhibitor is sufficient to block cells in mitosis ( Hoar et al ., 2007 ; Steegmaier et al ., 2007 ; Gleixner et al ., 2010 ; Grinshtein et al ., 2011 ; Fu et al ., 2012 ; Yuan et al ., 2012 ). Computer simulations support the idea that partial inhibition of both AURKA and Plk1 synergistically inhibit CDK1 activation ( Zou et al ., 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Stathmin and microtubules regulate mitotic entry in HeLa cells by controlling activation of both Aurora kinase A and Plk1

Silva

Cassimeris

2013

MBoC

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Section: Discussionmentioning

confidence: 99%

Stathmin and microtubules regulate mitotic entry in HeLa cells by controlling activation of both Aurora kinase A and Plk1

Silva

Cassimeris

2013

MBoC

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“…Finally, the pan-AURK inhibitor tozasertib not only causes cytokinesis defects through AURK inhibition but is also a potent inhibitor of necroptosis, a cell death process regulated and executed by the RIPK1, RIPK3, and MLKL signaling axis. Tozasertib may enhance carboplatin activity by MTT proliferative assay in both platinum-sensitive and platinum-resistant EOC cell lines, regardless of p53 status [ 56 ]. A low dose of tozasertib promotes paclitaxel-induced apoptosis and is effective in paclitaxel-resistant cells [ 57 ].…”

Section: Aurks In Ovarian Cancermentioning

confidence: 99%

Wise Management of Ovarian Cancer: On the Cutting Edge

Boussios

Mikropoulos

Samartzis

et al. 2020

JPM

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Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality among women. Two-thirds of patients present at advanced stage at diagnosis, and the estimated 5 year survival rate is 20–40%. This heterogeneous group of malignancies has distinguishable etiology and molecular biology. Initially, single-gene sequencing was performed to identify germline DNA variations associated with EOC. However, hereditary EOC syndrome can be explained by germline pathogenic variants (gPVs) in several genes. In this regard, next-generation sequencing (NGS) changed clinical diagnostic testing, allowing assessment of multiple genes simultaneously in a faster and cheaper manner than sequential single gene analysis. As we move into the era of personalized medicine, there is evidence that poly (ADP-ribose) polymerase (PARP) inhibitors exploit homologous recombination (HR) deficiency, especially in breast cancer gene 1 and 2 (BRCA1/2) mutation carriers. Furthermore, extensive preclinical data supported the development of aurora kinase (AURK) inhibitors in specific tumor types, including EOC. Their efficacy may be optimized in combination with chemotherapeutic or other molecular agents. The efficacy of metformin in ovarian cancer prevention is under investigation. Certain mutations, such as ARID1A mutations, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which are specific in ovarian clear cell carcinoma (OCCC) and endometrioid ovarian carcinoma (EnOC), may offer additional therapeutic targets in these clinical entities. Malignant ovarian germ cell tumors (MOGCTs) are rare and randomized trials are extremely challenging for the improvement of the existing management and development of novel strategies. This review attempts to offer an overview of the main aspects of ovarian cancer, catapulted from the molecular mechanisms to therapeutic considerations.

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“…It has been reported that AURKB inhibitors are able to enhance the cytotoxic effects of anticancer agents (19)(20)(21). Fu et al (19) reported that the AURK inhibitor VE 465 was able to enhance the antitumor activity of carboplatin in human ovarian cancer cells. Fiskus et al (20) used a combination treatment involving the pan-AURK inhibitor MK-0457 and vorinostat in human breast cancer cells, and demonstrated a synergistic effect in both in vitro and in vivo assays.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, AURKs are potential novel molecular targets for the prevention of cancer proliferation, and clinical trials have been performed (10). It has been reported that AURKB inhibitors are able to enhance the cytotoxic effects of anticancer agents (19)(20)(21). Fu et al (19) reported that the AURK inhibitor VE 465 was able to enhance the antitumor activity of carboplatin in human ovarian cancer cells.…”

Section: Discussionmentioning

confidence: 99%

In vitro evaluation of a combination treatment involving anticancer agents and an aurora kinase B inhibitor

et al. 2016

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Abstract. Aurora kinase B (AURKB) inhibitors are regarded as potential molecular-targeting drugs for cancer therapy. The present study evaluated the cytotoxic effect of a combination of AZD1152-hQPA, an AURKB inhibitor, and various anticancer agents on the HeLa human cervical cancer cell line, as well as its cisplatin-resistant equivalent HCP4 cell line. It was demonstrated that AZD1152-hQPA had an antagonistic effect on the cytotoxicity of cisplatin, etoposide and doxorubicin, but had a synergistic effect on that of all-trans-retinoic acid (ATRA), Am80 and TAC-101, when tested on HeLa cells. Cisplatin, etoposide and doxorubicin were shown to increase the cellular expression of AURKB, while ATRA, Am80 and TAC-101 downregulated its expression. These results suggested that AURKB expression is regulated by these anticancer agents at the transcriptional level, and that the level of expression of AURKB may influence the cytotoxic effect of AZD1152-hQPA. Therefore, when using anticancer agents, decreasing the expression of AURKB using a molecular-targeting drug may be an optimal therapeutic strategy. IntroductionThe human aurora kinase (AURK) family consists of three genes, including AURKA, AURKB and AURKC. Their gene products are located in different parts of the nucleus and have been suggested to function independently during the mitotic phase (M-phase) of the cell cycle (1-3). AURKB appears in the nucleus at the initial synthesis phase, and is involved in the regulation of cytokinesis by binding to several proteins containing the inhibitor Survivin (4,5). It has been reported that AURKs are overexpressed in tumor cells and, therefore, they are thought to be potential molecular targets for the treatment of malignant tumors (6-9). A number of inhibitors of AURK (ZM447439, VX-680, AT9283, AZD1152, MLN8054 and MLN8237) have been developed (6). These agents inhibit AURKA and AURKB to varying degrees, and some are currently in phase I clinical trials (10). The previously described inhibitor AZD1152 is a prodrug that changes to the active form AZD1152-hQPA in the cytoplasm, which has a dominant effect on AURKB (11).Chemotherapy using anticancer drugs, such as platinum-based therapies or taxanes, and radiotherapy are the most commonly employed strategies for the treatment of gynecological malignant tumors (12,13). AURK inhibitors are thought to be an effective molecular-targeting drug for gynecological malignant tumors (6), and clinical trials for their use against leukemia and other cancers are underway (10). In the future, there is a possibility that ARUK inhibitors may be used in combination with anticancer agents. However, it is unknown which anticancer agents would function most effectively in combination with AURK inhibitors. Sun et al (14) reported that the AURKB inhibitor, VX-680, downregulated nuclear factor (NF)-κB expression and increased the sensitivity of tumor cells to anticancer agents. Therefore, evaluation of the cellular expression or activity of NF-κB may emerge as an important basis for the use of AURK...

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Aurora kinase inhibitor VE 465 synergistically enhances cytotoxicity of carboplatin in ovarian cancer cells through induction of apoptosis and downregulation of histone 3

Cited by 13 publications

References 30 publications

Stathmin and microtubules regulate mitotic entry in HeLa cells by controlling activation of both Aurora kinase A and Plk1

Stathmin and microtubules regulate mitotic entry in HeLa cells by controlling activation of both Aurora kinase A and Plk1

Wise Management of Ovarian Cancer: On the Cutting Edge

In vitro evaluation of a combination treatment involving anticancer agents and an aurora kinase B inhibitor

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