ArticlePloS one2015
Cyclin-Dependent Kinase Inhibitor P1446A Induces Apoptosis in a JNK/p38 MAPK-Dependent Manner in Chronic Lymphocytic Leukemia B-Cells.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 36 citations in OpenAlex.
- The oral CDK9 inhibitor voruciclib combined with venetoclax for patients with relapsed/refractory acute myeloid leukemia.Blood neoplasia · 2025Article
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- A phase 1 study of the CDK9 inhibitor voruciclib in relapsed/refractory acute myeloid leukemia and B-cell malignancies.Blood advances · 2025Article
- The role of CD180 in hematological malignancies and inflammatory disorders.Molecular medicine (Cambridge, Mass.) · 2023Review
- Inhibition of p38 MAPK or immunoproteasome overcomes resistance of chronic lymphocytic leukemia cells to Bcl-2 antagonist venetoclax.Cell death & disease · 2022Article
- Implementation of a combined CDK inhibition and arginine-deprivation approach to target arginine-auxotrophic glioblastoma multiforme cells.Cell death & disease · 2022Article
- Pharmacologic Targeting of Mcl-1 Induces Mitochondrial Dysfunction and Apoptosis in B-Cell Lymphoma Cells in aClinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- Review
- Endoplasmic Reticulum Stress Contributes to Gefitinib-Induced Apoptosis in Glioma.International journal of molecular sciences · 2021Article
- CDK inhibitors in cancer therapy, an overview of recent development.American journal of cancer research · 2021Review
- Indoleamine 2,3-Dioxygenase Activity-Induced Acceleration of Tumor Growth, and Protein Kinases-Related Novel Therapeutics Regimens.Advances in experimental medicine and biology · 2021Article
- Anticancer Potential of Raddeanin A, a Natural Triterpenoid Isolated fromMolecules (Basel, Switzerland) · 2020Review
- Cell Death Pathways in Lymphoid Malignancies.Current oncology reports · 2020Review
- Article
- Positive transcription elongation factor b (P-TEFb) is a therapeutic target in human multiple myeloma.Oncotarget · 2017Article
- Dinaciclib Induces Anaphase Catastrophe in Lung Cancer Cells via Inhibition of Cyclin-Dependent Kinases 1 and 2.Molecular cancer therapeutics · 2016Article
- Autophagy Protects from Raddeanin A-Induced Apoptosis in SGC-7901 Human Gastric Cancer Cells.Evidence-based complementary and alternative medicine : eCAM · 2016Article
- Hepatocellular Carcinoma: Etiology and Current and Future Drugs.Journal of clinical and experimental hepatologyReview
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Authors and funding
9 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
CDK (cyclin-dependent kinase) inhibitors have shown remarkable activity in CLL, where its efficacy has been linked to inhibition of the transcriptional CDKs (7 and 9) and deregulation of RNA polymerase and short-lived pro-survival proteins such as MCL1. Furthermore, ER (endoplasmic reticulum) stress has been implicated in CDK inhibition in CLL. Here we conducted a pre-clinical study of a novel orally active kinase inhibitor P1446A in CLL B-cells. P1446A inhibited CDKs at nanomolar concentrations and induced rapid apoptosis of CLL cells in vitro, irrespective of chromosomal abnormalities or IGHV mutational status. Apoptosis preceded inactivation of RNA polymerase, and was accompanied by phosphorylation of stress kinases JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase). Pharmacologic inhibitors of JNK/p38 MAPK conferred protection from P1446A-mediated apoptosis. Treatment with P1446A led to a dramatic induction of NOXA in a JNK-dependent manner, and sensitized CLL cells to ABT-737, a BH3-mimetic. We observed concurrent activation of apoptosis stress-inducing kinase 1 (ASK1) and its interaction with inositol-requiring enzyme 1 (IRE1) and tumor necrosis factor receptor-associated factor 2 (TRAF2) in CLL cells treated with P1446A, providing insights into upstream regulation of JNK in this setting. Consistent with previous reports on limited functionality of ER stress mechanism in CLL cells, treatment with P1446A failed to induce an extensive unfolded protein response. This study provides rationale for additional investigations of P1446A in CLL.
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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.