Aurora kinase inhibitor enhances sensitivity of esophageal squamous cell carcinoma cells to cisplatin chemotherapy

Esophageal squamous cell carcinoma (ESCC) is malignant cancer with a high mortality rate. Cisplatin is one of the most potent chemotherapy agents used in the treatment of ESCC. However, chemoresistance and severe adverse effects of cisplatin become major obstacles to clinical utility. The combination treatment with molecule-targeted drugs and chemotherapy agents is a promising treatment strategy for cancer to improve antineoplastic responses. VX-680 is a potent inhibitor of Aurora kinases.
This study was performed to investigate if VX-680 and cisplatin can synergistically inhibit the malignant behavior of ESCC cells. The results obtained from 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide assay and combination index analysis demonstrated that the combination of VX-680 and cisplatin synergistically enhanced cytotoxic effects in ESCC cells. 2-(4-Amidinophenyl)-6-indolecarbamidine dihydrochloride staining and western blot analysis suggested that VX-680 increased cisplatin-mediated cell apoptosis.
Further analysis revealed that VX-680 combined with cisplatin could attenuate cell migration and angiogenesis confirmed by wound-healing assay and tube formation assay. Subsequently, VX-680 and cisplatin combined treatment significantly promoted cell-cell cohesion, and reduced cell-extracellular matrix interaction, as analyzed by the cell dissociation assay and cell-matrix attachment assay.
In addition, the combination of VX-680 and cisplatin markedly decreased the expressions of matrix metalloproteinases-2 (MMP-2), vascular endothelial growth factor (VEGF), p-extracellular signal-regulated protein kinase and p-RAC-α serine/threonine-protein kinase compared to VX-680 or cisplatin only treatment. Altogether, these findings strongly suggest that the combination of VX-680 and cisplatin could exert a synergistic antitumor effect in ESCC cells and this combination might represent a promising therapeutic strategy against ESCC.

Aurora kinase inhibitor suppresses the proliferation and migration of HUVECs and angiogenesis.

Angiogenesis serves a key role in tumor growth and metastasis. VX‑680, a potent inhibitor targeting the Aurora kinase family, is widely used in the inhibition of tumor progression. However, the effect of VX‑680 on angiogenesis remains unknown.
The present study identified that VX‑680 inhibited human umbilical vein endothelial cell (HUVEC) proliferation and promoted HUVEC apoptosis by inducing the cleavage of PARP and caspase‑3. VX‑680 also markedly decreased the migration and tube formation of HUVECs in a dose‑dependent manner.
In addition, VX‑680 significantly suppressed the formation of blood vessels in a dose‑dependent manner confirmed by a chicken embryo chorioallantoic membrane assay in vivo. Furthermore, VX‑680 inhibited the expression levels of vascular endothelial growth factor and phosphorylated RAC‑α serine/threonine‑protein kinase in HUVECs.
These results suggested that VX‑680 suppressed angiogenesis and may be a potential novel anti‑angiogenic agent.

RIPK1-dependent cell death: a novel target of the Aurora kinase inhibitor Tozasertib .

The Aurora kinase family (Aurora A, B and C) are crucial regulators of several mitotic events, including cytokinesis. Increased expression of these kinases is associated with tumorigenesis and several compounds targeting Aurora kinase are under evaluation in clinical trials (a.o. AT9283, AZD1152, Danusertib, MLN8054).
Here, we demonstrate that the pan-Aurora kinase inhibitor Tozasertib (VX-680 and MK-0457) not only causes cytokinesis defects through Aurora kinase inhibition, but is also a potent inhibitor of necroptosis, a cell death process regulated and executed by the RIPK1, RIPK3 and MLKL signalling axis.
Tozasertib’s potency to inhibit RIPK1-dependent necroptosis and to block cytokinesis in cells is in the same concentration range, with an IC50 of 1.06 µM and 0.554 µM, respectively. A structure-activity relationship (SAR) analysis of 67 Tozasertib analogs, modified at 4 different positions, allowed the identification of analogues that showed increased specificity for either cytokinesis inhibition or for necroptosis inhibition, reflecting more specific inhibition of Aurora kinase or RIPK1, respectively.
These results also suggested that RIPK1 and Aurora kinases are functionally non-interacting targets of Tozasertib and its analogues.
Indeed, more specific Aurora kinase inhibitors did not show any effect in necroptosis and Necrostatin-1s treatment did not result in cytokinesis defects, demonstrating that both cellular processes are not interrelated.
Finally, Tozasertib inhibited recombinant human RIPK1, human Aurora A and human Aurora B kinase activity, but not RIPK3.
The potency ranking of the newly derived Tozasertib analogues and their specificity profile, as observed in cellular assays, coincide with ADP-Glo recombinant kinase activity assays. Overall, we show that Tozasertib not only targets Aurora kinases but also RIPK1 independently, and that we could generate analogues with increased selectivity to RIPK1 or Aurora kinases, respectively.

induces p53-mediated apoptosis in human cholangiocarcinoma cells.

VX-680 is one selective small-molecule inhibitor of the Aurora kinases. It has been shown to disrupt motosis and induce apoptosis in a wide variety of tumor cell lines. However, its effect on human cholangiocarcinoma (CCA) cells remains uncharacterized. In the current study, we observed the effects of VX-680 on the human CCA (QBC939 and HCCC-9810) cell line.
In cell culture, VX-680 inhibited proliferation and induced apoptosis of tumor cell growth in a dose-dependent and time-dependent manner, and exerted the most effective cytotoxicity against HCCC-9810 cells. The proliferation inhibition rate increased from 5.39 to 51.74%, whereas the apoptosis rate increased from 9.59 to 50.02% when HCCC-9810 cells were cultured with 5 µmol/l VX-680 for 48 h.
Immunoblot analysis showed that the expression of phospho-p53(Ser-15) was upregulated after 48 h treatment of the cancer cells with VX-680. This activation in p53 was associated with a decrease in Bcl-2 and an increase in Bax, which led to the expression of its downstream effectors (caspase-9 and caspase-3). We further found that pifithrin-α, a p53 inhibitor, attenuated the anticancer effects of VX-680 and downregulated the expression of apotosis-related proteins (Bax and caspase-9).
These results suggest that VX-680 could mediate cell death by acting on a P53/Bax/ caspase-3-dependent pathway in human CCA cells.

The aurora kinase inhibitor shows anti-cancer effects in primary metastatic cells and the SW13 cell line.

New therapeutic targets are needed to fight cancer. Aurora kinases (AK) were recently identified as vital key regulators of cell mitosis and have consequently been investigated as therapeutic targets in preclinical and clinical studies.
Aurora kinase inhibitors (AKI) have been studied in many cancer types, but their potential capacity to limit or delay metastases has rarely been considered, and never in adrenal tissue. Given the lack of an effective pharmacological therapy for adrenal metastasis and adrenocortical carcinoma, we assessed AKI (VX-680, SNS314, ZM447439) in 2 cell lines (H295R and SW13 cells), 3 cell cultures of primary adrenocortical metastases (from lung cancer), and 4 primary adrenocortical tumor cell cultures.
We also tested reversan, which is a P-gp inhibitor (a fundamental efflux pump that can extrude drugs), and we measured AK expression levels in 66 adrenocortical tumor tissue samples. Biomolecular and cellular tests were performed (such as MTT, thymidine assay, Wright’s staining, cell cycle and apoptosis analysis, Western blot, qRT-PCR, and mutation analysis). Our results are the first to document AK overexpression in adrenocortical carcinoma as well as in H295R and SW13 cell lines, thus proving the efficacy of AKI against adrenal metastases and in the SW13 cancer cell model.
We also demonstrated that reversan and AKI Vx-680 are useless in the H295R cell model, and therefore should not be considered as potential treatments for ACC. Serine/threonine AK inhibition, essentially with VX-680, could be a promising, specific therapeutic tool for eradicating metastases in adrenocortical tissue.

SMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor in non-small cell lung cancers.

Mutations in the SMARCA4/BRG1 gene resulting in complete loss of its protein (BRG1) occur frequently in non-small cell lung cancer (NSCLC) cells. Currently, no single therapeutic agent has been identified as synthetically lethal with SMARCA4/BRG1 loss.

VX-680 (MK-0457)

E1KS1048 EnoGene 25 mg 247 EUR

VX-680 (MK-0457, Tozasertib)

M73000 EpiGentek 25 mg 192.1 EUR

VX-680 (MK-0457,Tozasertib)

A4111-100 ApexBio 100 mg 166 EUR

VX-680 (MK-0457,Tozasertib)

A4111-250 ApexBio 250 mg 282 EUR

VX-680 (MK-0457,Tozasertib)

A4111-5.1 ApexBio 10 mM (in 1mL DMSO) 125 EUR

VX-680 (MK-0457,Tozasertib)

A4111-50 ApexBio 50 mg 119 EUR

Tozasertib (VX-680, MK-0457, VX6)

1595-100 Biovision 387 EUR

Tozasertib (VX-680, MK-0457, VX6)

1595-25 Biovision 158 EUR

VX-11e

HY-14178 MedChemExpress 50mg 601 EUR

VX-984

HY-19939S MedChemExpress 10mM/1mL 744 EUR

VX-222

HY-75800 MedChemExpress 10mM/1mL 201 EUR

VX-702

HY-10401 MedChemExpress 10mM/1mL 126 EUR

VX-702

E1KS6005 EnoGene 25mg1​ PHYSICAL AND CHEMICAL PROPERTIES 325 EUR

VX-770

E1KS1144 EnoGene 5mg 1111 EUR

VX-745

E1KS1458 EnoGene 10mg 1934 EUR

VX-222

E1KS1480 EnoGene 5mg 874 EUR

VX-809

E1KS1565 EnoGene 10mg 1897 EUR

Vx-770

20-abx182704 Abbexa
  • 1525.00 EUR
  • 565.00 EUR
  • 100 mg
  • 10 mg

VX-765

A8238-10 ApexBio 10 mg 166 EUR

VX-765

A8238-100 ApexBio 100 mg 572 EUR

VX-765

A8238-5 ApexBio 5 mg 131 EUR

VX-765

A8238-5.1 ApexBio 10 mM (in 1mL DMSO) 148 EUR
We identify AURKA activity as essential in NSCLC cells lacking SMARCA4/BRG1. In these cells, RNAi-mediated depletion or chemical inhibition of AURKA induces apoptosis and cell death in vitro and in xenograft mouse models.
Disc large homologue-associated protein 5 (HURP/DLGAP5), required for AURKA-dependent, the centrosome-independent mitotic spindle assembly is essential for the survival and proliferation of SMARCA4/BRG1 mutant but not of SMARCA4/BRG1 wild-type cells. AURKA inhibitors may provide a therapeutic strategy for biomarker-driven clinical studies to treat the NSCLCs harbouring SMARCA4/BRG1-inactivating mutations.

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