ArticleGenes & cancer2010
CDK Inhibitors Roscovitine and CR8 Trigger Mcl-1 Down-Regulation and Apoptotic Cell Death in Neuroblastoma Cells.
Article in Genes & cancer, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 84 citations in OpenAlex.
- CDK9 inhibitor A09-003 overcomes TRAIL resistance via dual Mcl-1 suppression in breast cancer cells.Discover oncology · 2026Article
- A patent review of cyclin-dependent kinase 5 (CDK5) inhibitors (1999-2025).Frontiers in bioengineering and biotechnology · 2026Review
- DDB1 engagement defines the selectivity of S656 analogs for cyclin K degradation over CDK inhibition.EMBO reports · 2025Article
- SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis.Molecular cell · 2025Article
- Development and Validation of a New Eco-Friendly HPLC-PDA Bioanalytical Method for Studying Pharmacokinetics of Seliciclib.Medicina (Kaunas, Lithuania) · 2024Article
- A Simple Eco-Friendly HPLC-PDA Method for the Simultaneous Determination of Paclitaxel and Seliciclib in Plasma Samples for Assessing Their Pharmacodynamics and Pharmacokinetics in Combination Therapy for Uterine Sarcoma.Medicina (Kaunas, Lithuania) · 2024Article
- Genetic impairment of succinate metabolism disrupts bioenergetic sensing in adrenal neuroendocrine cancer.Cell reports · 2022Article
- Exploration of the Detailed Structure-Activity Relationships of Isatin and Their Isomers As Monoamine Oxidase Inhibitors.ACS omega · 2022Review
- Therapeutic Potential of the Cyclin-Dependent Kinase Inhibitor Flavopiridol on c-Myc Overexpressing Esophageal Cancer.Frontiers in pharmacology · 2021Article
- The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents.Molecules (Basel, Switzerland) · 2020Review
- CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells.Cell death & disease · 2020Article
- Pharmacological Inhibition of Cyclin-Dependent Kinases Triggers Anti-Fibrotic Effects in Hepatic Stellate Cells In Vitro.International journal of molecular sciences · 2020Article
- Systemic Administration of the Cyclin-Dependent Kinase Inhibitor (S)-CR8 Selectively Reduces Escalated Ethanol Intake in Dependent Rats.Alcoholism, clinical and experimental research · 2019Article
- Computational Simulations Identify Pyrrolidine-2,3-Dione Derivatives as Novel Inhibitors of Cdk5/p25 Complex to Attenuate Alzheimer's Pathology.Journal of clinical medicine · 2019Article
- Comparing effects of CDK inhibition and E2F1/2 ablation on neuronal cell death pathways in vitro and after traumatic brain injury.Cell death & disease · 2018Article
- Casein kinase 1ε and 1α as novel players in polycystic kidney disease and mechanistic targets for (R)-roscovitine and (S)-CR8.American journal of physiology. Renal physiology · 2018Article
- MCL-1 inhibition in cancer treatment.OncoTargets and therapy · 2018Review
- Genetic and pharmacological inhibition of Cdk1 provides neuroprotection towards ischemic neuronal death.Cell death discovery · 2018Article
- Identification of novel inhibitors against Cyclin Dependent Kinase 9/Cyclin T1 complex as: Anti cancer agent.Saudi journal of biological sciences · 2017Article
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Authors and funding
12 authors at 5 institutions in 2 countries.
Funding
Abstract
Neuroblastoma (NB), the most frequent extracranial solid tumor of children accounting for nearly 15% of all childhood cancer mortality, displays overexpression of antiapoptotic Bcl-2 and Mcl-1 in aggressive forms of the disease. The clinical phase 2 drug roscovitine (CYC202, seliciclib), a relatively selective inhibitor of cyclin-dependent kinases (CDKs), and CR8, a recently developed and more potent analog, induce concentration-dependent apoptotic cell death of NB cells (average IC(50) values: 24.2 µM and 0.4 µM for roscovitine and CR8, respectively). Both roscovitine and CR8 trigger rapid down-regulation of the short-lived survival factor Mcl-1 in the 9 investigated human NB cell lines. This effect was further analyzed in the human SH-SY5Y NB cell line. Down-regulation of Mcl-1 appears to depend on inhibition of CDKs rather than on interaction of roscovitine and CR8 with their secondary targets. CR8 is an adenosine triphosphate-competitive inhibitor of CDK9, and the structure of a CDK9/cyclin T/CR8 complex is described. Mcl-1 down-regulation occurs both at the mRNA and protein levels. This effect can be accounted for by a reduction in Mcl-1 protein synthesis, under stable Mcl-1 degradation conditions. Mcl-1 down-regulation is accompanied by a transient increase in free Noxa, a proapoptotic factor. Mcl-1 down-regulation occurs independently of the presence or up-regulation of p53 and of the MYCN status. Taken together, these results suggest that the clinical drug roscovitine and its novel analog CR8 induce apoptotic tumor cell death by down-regulating Mcl-1, a key survival factor expressed in all NB cell lines. CDK inhibition may thus constitute a new approach to treat refractory high-risk NB.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.