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Drug Design, Development and Therapy 2015Gastric cancer is the second leading cause of cancer-related death worldwide, with a poor response to current chemotherapy. Danusertib is a pan-inhibitor of the Aurora...
Danusertib, a potent pan-Aurora kinase and ABL kinase inhibitor, induces cell cycle arrest and programmed cell death and inhibits epithelial to mesenchymal transition involving the PI3K/Akt/mTOR-mediated signaling pathway in human gastric cancer AGS and NCI-N78 cells.
Gastric cancer is the second leading cause of cancer-related death worldwide, with a poor response to current chemotherapy. Danusertib is a pan-inhibitor of the Aurora kinases and a third-generation Bcr-Abl tyrosine kinase inhibitor with potent anticancer effects, but its antitumor effect and underlying mechanisms in the treatment of human gastric cancer are unknown. This study aimed to investigate the effects of danusertib on cell growth, apoptosis, autophagy, and epithelial to mesenchymal transition and the molecular mechanisms involved in human gastric cancer AGS and NCI-N78 cells. The results showed that danusertib had potent growth-inhibitory, apoptosis-inducing, and autophagy-inducing effects on AGS and NCI-N78 cells. Danusertib arrested AGS and NCI-N78 cells in G2/M phase, with downregulation of expression of cyclin B1 and cyclin-dependent kinase 1 and upregulation of expression of p21 Waf1/Cip1, p27 Kip1, and p53. Danusertib induced mitochondria-mediated apoptosis, with an increase in expression of proapoptotic protein and a decrease in antiapoptotic proteins in both cell lines. Danusertib induced release of cytochrome c from the mitochondria to the cytosol and triggered activation of caspase 9 and caspase 3 in AGS and NCI-N78 cells. Further, danusertib induced autophagy, with an increase in expression of beclin 1 and conversion of microtubule-associated protein 1A/1B-light chain 3 (LC3-I) to LC3-II in both cell lines. Inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase pathways as well as activation of 5' AMP-activated protein kinase contributed to the proautophagic effect of danusertib in AGS and NCI-N78 cells. SB202191 and wortmannin enhanced the autophagy-inducing effect of danusertib in AGS and NCI-N78 cells. In addition, danusertib inhibited epithelial to mesenchymal transition with an increase in expression of E-cadherin and a decrease in expression of N-cadherin in both cell lines. Taken together, danusertib has potent inducing effects on cell cycle arrest, apoptosis, and autophagy, but has an inhibitory effect on epithelial to mesenchymal transition, with involvement of signaling pathways mediated by PI3K/Akt/mTOR, p38 mitogen-activated protein kinase, and 5' AMP-activated protein kinase in AGS and NCI-N78 cells.
Topics: Antineoplastic Agents; Apoptosis; Aurora Kinases; Benzamides; Cell Cycle Checkpoints; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Epithelial-Mesenchymal Transition; Humans; Molecular Structure; Phosphatidylinositol 3-Kinase; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-abl; Proto-Oncogene Proteins c-akt; Pyrazoles; Signal Transduction; Stomach Neoplasms; Structure-Activity Relationship; TOR Serine-Threonine Kinases; Tumor Cells, Cultured
PubMed: 25767376
DOI: 10.2147/DDDT.S74964 -
Journal of Cancer Research and... 2021Pancreatic cancer is the second type of cancer that causes the most death among the digestive system cancers. Difficulties in early diagnosis and rapidly progressing to...
BACKGROUND
Pancreatic cancer is the second type of cancer that causes the most death among the digestive system cancers. Difficulties in early diagnosis and rapidly progressing to advanced stages are most common in high mortality rate of pancreatic carcinoma. The mutation of Bcr-Abl tyrosine kinase and mitotic kinases (such as Aurora kinases), which are involved in the cell cycle, plays an important role in the progression of cancer. Enzymes belonging to Aurora kinase family (-A, -B, -C) have been reported to play a major role in cancer progression, invasion and metastasis. Therefore, the purpose of this study, investigate of the effect of danusertib, an Aurora kinase inhibitor, onto cytotoxicity, apoptosis and cell cycle in human pancreatic carcinoma CFPAC-1 cells.
MATERIALS AND METHODS
For determining the IC50 value, the 20,000 cells were seeded in E-plate 16 wells in a real-time cell analyzer and various concentrations of danusertib (1-10,000 nM) were applied onto CFPAC-1 cells incubated in IMDM medium. Cell index demonstrated that the proliferation of fraction cells was measured in real time. On the other hand, cell apoptosis and cell cycle arrest test were stained with Annexin V-APC/PI and DNA-cell cycle PI staining respectively by using flow cytometry.
RESULTS
The IC value was found to be approximately 400 nM. Danusertib at this concentration induced apoptosis in CFPAC-1 cells (%14,8 at 24 hours; %21,3 at 48 hours). Furthermore, in the cells treated with danusertib, 31.77% and 11.05% were arrested in the S and G2 phases, respectively.
CONCLUSIONS
Aurora kinase inhibitor danusertib induced a significant effect of cytotoxic, apoptotic and cell cycle arrest in CFPAC-1 ductal adenocarcinoma cells. Therefore, it may be a potential alternative to the treatment of pancreatic cancers.
Topics: Apoptosis; Aurora Kinases; Benzamides; Carcinoma, Pancreatic Ductal; Cell Cycle Checkpoints; Cell Proliferation; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Pancreatic Neoplasms; Pyrazoles; Tumor Cells, Cultured
PubMed: 34916372
DOI: 10.4103/jcrt.JCRT_827_19 -
Investigational New Drugs Oct 2011Danusertib is a serine/threonine kinase inhibitor of multiple kinases, including aurora-A, B, and C. This explorative study aims to identify possible relationships...
OBJECTIVES
Danusertib is a serine/threonine kinase inhibitor of multiple kinases, including aurora-A, B, and C. This explorative study aims to identify possible relationships between single nucleotide polymorphisms in genes coding for drug metabolizing enzymes and transporter proteins and clearance of danusertib, to clarify the interpatient variability in exposure. In addition, this study explores the relationship between target receptor polymorphisms and toxicity of danusertib.
METHODS
For associations with clearance, 48 cancer patients treated in a phase I study were analyzed for ABCB1, ABCG2 and FMO3 polymorphisms. Association analyses between neutropenia and drug target receptors, including KDR, RET, FLT3, FLT4, AURKB and AURKA, were performed in 30 patients treated at recommended phase II dose-levels in three danusertib phase I or phase II trials.
RESULTS
No relationships between danusertib clearance and drug metabolizing enzymes and transporter protein polymorphisms were found. Only, for the one patient with FMO3 18281AA polymorphism, a significantly higher clearance was noticed, compared to patients carrying at least 1 wild type allele. No effect of target receptor genotypes or haplotypes on neutropenia was observed.
CONCLUSIONS
As we did not find any major correlations between pharmacogenetic variability in the studied enzymes and transporters and pharmacokinetics nor toxicity, it is unlikely that danusertib is highly susceptible for pharmacogenetic variation. Therefore, no dosing alterations of danusertib are expected in the future, based on the polymorphisms studied. However, the relationship between FMO3 polymorphisms and clearance of danusertib warrants further research, as we could study only a small group of patients.
Topics: Adult; Aged; Analysis of Variance; Antineoplastic Agents; Aurora Kinase A; Aurora Kinase B; Aurora Kinases; Benzamides; Female; Haplotypes; Humans; Male; Middle Aged; Neoplasm Grading; Pharmacogenetics; Polymorphism, Genetic; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrazoles; Young Adult
PubMed: 20182906
DOI: 10.1007/s10637-010-9405-7 -
Annals of Oncology : Official Journal... Mar 2015This multi-centre phase II trial assessed the activity, safety (CTCAE 3.0) and pharmacokinetics (PK) of the pan-Aurora kinase inhibitor danusertib hydrochloride...
Efficacy and safety of biweekly i.v. administrations of the Aurora kinase inhibitor danusertib hydrochloride in independent cohorts of patients with advanced or metastatic breast, ovarian, colorectal, pancreatic, small-cell and non-small-cell lung cancer: a multi-tumour, multi-institutional phase...
BACKGROUND
This multi-centre phase II trial assessed the activity, safety (CTCAE 3.0) and pharmacokinetics (PK) of the pan-Aurora kinase inhibitor danusertib hydrochloride (PHA-739358) in breast (BC), ovarian (OC), pancreatic (PC), colorectal (CRC), small-cell (SCLC) and non-small-cell lung (NSCLC) cancers.
METHODS
Consenting adult patients with good performance and organ function with advanced/metastatic tumours who had failed systemic therapy were treated in independent, disease-specific cohorts with danusertib 500 mg/m(2) given as 24-h i.v. infusion every 14 days with until progression or unacceptable toxicity. A two-stage design was applied. Primary end point was the progression-free rate (PFR) at 4 months (RECIST1.1).
RESULTS
A total of 223 patients were enrolled with 219 actively treated. The median relative dose intensity of danusertib was similar for all tumour types (84.6%-99.6%). The median number of biweekly treatment cycles ranged from 3 to 4/patient (maximum 5-40 cycles/entity) and the median treatment duration varied between 7.6 and 10.0 weeks per histotype. Danusertib did not meet pre-specified protocol criteria for clinically relevant activity in any of the treated cancers. The PFR at 4 months was 18.4% in BC, 12.1% in OC, 10.0% in PC, 10.4% in NSCLC (all histotypes), 16.1% in squamous NSCLC and 0% in SCLC and CRC. Some radiological and/or biochemical indication of antitumor activity was seen in BC, OC, PC and NSCLC, including two confirmed partial responses. The most frequent drug-related non-laboratory adverse events (AEs) were fatigue/asthenia, nausea, diarrhoea, anorexia, vomiting, alopecia, constipation and pyrexia. Common laboratory AEs included haematological toxicity, hypalbuminaemia and increases in liver enzymes. Treatment was discontinued due to AEs in only 5.5% of patients. Plasma concentrations of danusertib were in line with results from earlier studies.
CONCLUSION
Single-agent danusertib did show only marginal anti-tumour activity in common solid tumours after failure of prior systemic therapies. The safety and PK profile was consistent with previous experience.
CLINICAL TRIAL NUMBER
2006-003772-35.
Topics: Administration, Intravenous; Aged; Aurora Kinases; Benzamides; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Cohort Studies; Colorectal Neoplasms; Drug Administration Schedule; Female; Humans; Lung Neoplasms; Male; Middle Aged; Ovarian Neoplasms; Prospective Studies; Protein Kinase Inhibitors; Pyrazoles; Small Cell Lung Carcinoma; Treatment Outcome
PubMed: 25488684
DOI: 10.1093/annonc/mdu566 -
Frontiers in Oncology 2022In chronic myeloid leukemia (CML), Aurora kinase A and Polo like kinase 1 (PLK1), two serine-threonine kinases involved in the maintenance of genomic stability by...
Polo-like kinase-1, Aurora kinase A and WEE1 kinase are promising druggable targets in CML cells displaying BCR::ABL1-independent resistance to tyrosine kinase inhibitors.
In chronic myeloid leukemia (CML), Aurora kinase A and Polo like kinase 1 (PLK1), two serine-threonine kinases involved in the maintenance of genomic stability by preserving a functional G2/M checkpoint, have been implicated in BCR::ABL1-independent resistance to the tyrosine kinase inhibitor (TKI) imatinib mesylate and in leukemic stem cell (LSC) persistence. It can be speculated that the observed deregulated activity of Aurora A and Plk1 enhances DNA damage, promoting the occurrence of additional genomic alterations contributing to TKI resistance and ultimately driving progression from chronic phase to blast crisis (BC). In this study, we propose a new therapeutic strategy based on the combination of Aurora kinase A or PLK1 inhibition with danusertib or volasertib, respectively, and WEE1 inhibition with AZD1775. Danusertib and volasertib used as single drugs induced apoptosis and G2/M-phase arrest, associated with accumulation of phospho-WEE1. Subsequent addition of the WEE1 inhibitor AZD1775 in combination significantly enhanced the induction of apoptotic cell death in TKI-sensitive and -resistant cell lines as compared to both danusertib and volasertib alone and to the simultaneous combination. This schedule indeed induced a significant increase of the DNA double-strand break marker γH2AX, forcing the cells through successive replication cycles ultimately resulting in apoptosis. Finally, combination of danusertib or volasertib+AZD1775 significantly reduced the clonogenic potential of CD34+ CML progenitors from BC patients. Our results may have implications for the development of innovative therapeutic approaches aimed to improve the outcomes of patients with multi-TKI-resistant or BC CML.
PubMed: 35992847
DOI: 10.3389/fonc.2022.901132 -
Postepy Higieny I Medycyny... Dec 2011Recently novel treatment modalities has focused on targeted therapies. Tyrosine kinases represent a good target for cancer treatment since they are involved in... (Review)
Review
Recently novel treatment modalities has focused on targeted therapies. Tyrosine kinases represent a good target for cancer treatment since they are involved in transferring phosphate groups from ATP to tyrosine residues in specific substrate proteins transducing intracellular signals engaged in the many mechanisms, playing an important role in the modulation of growth factors signaling that are strongly related to carcinogenesis. Deregulation of tyrosine kinases activity was also found in hematological malignancies, particularly overexpression of tyrosine kinases was observed in chronic myeloid leukemia or acute lymphoblastic leukemia. Herein we show that tyrosine kinase inhibitors have revolutionized hematology malignancies therapy in a very short period of time and they still remain one of the most interesting anticancer compounds that could give a hope for cure and not only long-lasting complete remission. This manuscript summarizes current view on the first generation tyrosine kinase inhibititor--imatinib, second generation--dasatinib, nilotinib and bosutnib as well as new generation tyrosine kinase inhibititors--ponatinib and danusertib in hematooncology.
Topics: Aniline Compounds; Antineoplastic Agents; Benzamides; Dasatinib; Hematologic Neoplasms; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Nitriles; Piperazines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein-Tyrosine Kinases; Pyrimidines; Quinolines; Thiazoles
PubMed: 22173446
DOI: 10.5604/17322693.968778 -
Drug Design, Development and Therapy 2015Danusertib (Danu) is a pan-inhibitor of Aurora kinases and a third-generation breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (Bcr-Abl)...
Danusertib (Danu) is a pan-inhibitor of Aurora kinases and a third-generation breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (Bcr-Abl) tyrosine kinase inhibitor, but its antitumor effect and underlying mechanisms in the treatment of human breast cancer remain elusive. This study aimed to investigate the effects of Danu on the growth, apoptosis, autophagy, and epithelial-to-mesenchymal transition (EMT) and the molecular mechanisms in human breast cancer MCF7 and MDA-MB-231 cells. The results demonstrated that Danu remarkably inhibited cell proliferation, induced apoptosis and autophagy, and suppressed EMT in both breast cancer cell lines. Danu arrested MCF7 and MDA-MB-231 cells in G2/M phase, accompanied by the downregulation of cyclin-dependent kinase 1 and cyclin B1 and upregulation of p21 Waf1/Cip1, p27 Kip1, and p53. Danu significantly decreased the expression of B-cell lymphoma-extra-large (Bcl-xl) and B-cell lymphoma 2 (Bcl-2), but increased the expression of Bcl-2-associated X protein (Bax) and p53-upregulated modulator of apoptosis (PUMA), and promoted the cleavage of caspases 3 and 9. Furthermore, Danu significantly increased the expression levels of the membrane-bound microtubule-associated protein 1A/1B-light chain 3 (LC3-II) and beclin 1 in breast cancer cells, two markers for autophagy. Danu induced the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases 1 and 2 (Erk1/2) and inhibited the activation of protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways in breast cancer cells. Treatment with wortmannin (a phosphatidylinositol 3-kinase inhibitor) markedly inhibited Danu-induced activation of p38 MAPK and conversion of cytosolic LC3-I to membrane-bound LC3-II. Pharmacological inhibition and small interfering RNA-mediated knockdown of p38 MAPK suppressed Akt activation, resulting in LC3-II accumulation and enhanced autophagy. Pharmacological inhibition and small interfering RNA-mediated knockdown of Erk1/2 also remarkably increased the level of LC3-II in MCF7 cells. Moreover, Danu inhibited EMT in both MCF7 and MDA-MB-231 cells with upregulated E-cadherin and zona occludens protein 1 (ZO-1) but downregulated N-cadherin, zinc finger E-box-binding homeobox 1 (TCF8/ZEB1), snail, slug, vimentin, and β-catenin. Notably, Danu showed lower cytotoxicity toward normal breast epithelial MCF10A cells. These findings indicate that Danu promotes cellular apoptosis and autophagy but inhibits EMT in human breast cancer cells via modulation of p38 MAPK/Erk1/2/Akt/mTOR signaling pathways. Danu may represent a promising anticancer agent for breast cancer treatment. More studies are warranted to fully delineate the underlying mechanisms, efficacy, and safety of Danu in breast cancer therapy.
Topics: Apoptosis; Aurora Kinases; Autophagy; Benzamides; Breast Neoplasms; Cell Cycle; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Epithelial-Mesenchymal Transition; Humans; MCF-7 Cells; Molecular Structure; Protein Kinase Inhibitors; Pyrazoles; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 25733818
DOI: 10.2147/DDDT.S74412 -
Journal of Hematology & Oncology Jun 2018Bcr-Abl inhibitors paved the way of targeted therapy epoch. Imatinib was the first tyrosine kinase inhibitor to be discovered with high specificity for Bcr-Abl protein... (Review)
Review
Bcr-Abl inhibitors paved the way of targeted therapy epoch. Imatinib was the first tyrosine kinase inhibitor to be discovered with high specificity for Bcr-Abl protein resulting from t(9, 22)-derived Philadelphia chromosome. Although the specific targeting of that oncoprotein, several Bcr-Abl-dependent and Bcr-Abl-independent mechanisms of resistance to imatinib arose after becoming first-line therapy in chronic myelogenous leukemia (CML) treatment.Consequently, new specific drugs, namely dasatinib, nilotinib, bosutinib, and ponatinib, were rationally designed and approved for clinic to override resistances. Imatinib fine mechanisms of action had been elucidated to rationally develop those second- and third-generation inhibitors. Crystallographic and structure-activity relationship analysis, jointly to clinical data, were pivotal to shed light on this topic. More recently, preclinical evidence on bafetinib, rebastinib, tozasertib, danusertib, HG-7-85-01, GNF-2, and 1,3,4-thiadiazole derivatives lay promising foundations for better inhibitors to be approved for clinic in the near future.Notably, structural mechanisms of action and drug design exemplified by Bcr-Abl inhibitors have broad relevance to both break through resistances in CML treatment and develop inhibitors against other kinases as targeted chemotherapeutics.
Topics: Fusion Proteins, bcr-abl; Humans; Molecular Targeted Therapy; Protein Kinase Inhibitors; Structure-Activity Relationship; Treatment Outcome
PubMed: 29925402
DOI: 10.1186/s13045-018-0624-2 -
Haematologica Jul 2015Danusertib is a pan-aurora kinase inhibitor with potent activity against Abl kinase including the gatekeeper T315I mutant. A phase 1 dose escalation study of danusertib...
A phase I study of danusertib (PHA-739358) in adult patients with accelerated or blastic phase chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to imatinib and/or other second generation c-ABL therapy.
Danusertib is a pan-aurora kinase inhibitor with potent activity against Abl kinase including the gatekeeper T315I mutant. A phase 1 dose escalation study of danusertib was conducted in patients with accelerated or blastic phase chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Two dosing schedules were studied: schedule A, in which danusertib was given by 3-hour intravenous infusion daily for 7 consecutive days (days 1-7) in a 14-day cycle, and schedule B, in which the danusertib was given by 3-hour intravenous infusion daily for 14 consecutive days (days 1-14) in a 21-day cycle. A total of 37 patients were treated, 29 with schedule A and eight with schedule B. The recommended phase 2 dose for schedule A was 180 mg/m(2). Enrollment to schedule B was stopped early because of logistical problems with the frequency of infusions. Febrile neutropenia and mucositis were dose-limiting toxicities in schedule A. Four patients with T315I ABL kinase mutation, all treated with schedule A, responded. Danusertib has an acceptable toxicity profile and is active in patients with Bcr-Abl-associated advanced hematologic malignancies. This study was registered with the European Clinical Trails Data Base (EudraCT number 2007-004070-18).
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Benzamides; Blast Crisis; Drug Administration Schedule; Febrile Neutropenia; Female; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; Leukemia, Myeloid, Accelerated Phase; Male; Middle Aged; Mucositis; Mutation; Philadelphia Chromosome; Protein Kinase Inhibitors; Pyrazoles
PubMed: 25887498
DOI: 10.3324/haematol.2014.115279 -
The Turkish Journal of Gastroenterology... Feb 2024Pancreatic ductal adenocarcinoma is an extremely deadly type of cancer with a high metastatic potential. Genetic factors in cellular events play an important role in the...
BACKGROUND/AIMS
Pancreatic ductal adenocarcinoma is an extremely deadly type of cancer with a high metastatic potential. Genetic factors in cellular events play an important role in the emergence of this situation. One of these factors is Aurora kinase family members, which play a role in migration, invasion, and cell cycle. In this study, the expression of vascular endothelial growth factor gene, which plays a role in migration, metastasis, and angiogenesis, on cystic fibrosis human pancreatic ductal adenocarcinoma 1 cells of danusertib, a pan-Aurora kinase inhibitor, was examined.
MATERIALS AND METHODS
The half maximal inhibitory concentration (IC50) value (400 nM) of danusertib in cystic fibrosis human pancreatic ductal adenocarcinoma 1 cells was determined by the wound-healing test depending on the dose and time and migration with CIM-Plate 16 in the xCELLingence system. In addition, the effect of danusertib on migration was determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) method and vascular endothelial growth factor gene expression.
RESULTS
When the dose- and time-dependent danusertib-applied cystic fibrosis human pancreatic ductal adenocarcinoma 1 cells were compared with the control group, it was observed that the wound formed did not close. In the xCELLigence system CIM-Plate 16 migration analysis, it was observed that migration was inhibited in the group administered danusertib in parallel with the wound dehiscence experiment. The gene expressions of vascular endothelial growth factor decreased 0.5-fold at the 24th hour and 0.3-fold at the 48th hour in the Danusertib-administered groups.
CONCLUSION
Danusertib, a pan-Aurora kinase inhibitor, is predicted to be used as a potential agent in pancreatic cancers due to its antitumor and anti-metastatic effect.
Topics: Humans; Vascular Endothelial Growth Factor A; Adenocarcinoma; Pancreatic Neoplasms; Cystic Fibrosis; Aurora Kinases; Protein Kinase Inhibitors; Cell Proliferation; Benzamides; Pyrazoles
PubMed: 38454247
DOI: 10.5152/tjg.2024.22319