ArticleCell cycle (Georgetown, Tex.)2010
Inhibition of Cot1/Tlp2 oncogene in AML cells reduces ERK5 activation and up-regulates p27Kip1 concomitant with enhancement of differentiation and cell cycle arrest induced by silibinin and 1,25-dihydroxyvitamin D(3).
Article in Cell cycle (Georgetown, Tex.), 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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25 citing papers in PubMed, 47 citations in OpenAlex.
- Vitamin D Deficiency in Leukemia: Implications for Pathophysiology, Treatment, and Supportive Care.Nutrients · 2026Review
- Improving the Antitumor Effect of Chemotherapy with Ocoxin as a Novel Adjuvant Agent to Treat Prostate Cancer.Nutrients · 2023Article
- Structure-Activity Relationship of Hydroxycinnamic Acid Derivatives for Cooperating with Carnosic Acid and Calcitriol in Acute Myeloid Leukemia Cells.Biomedicines · 2021Article
- The anti-cancer drug ABTL0812 induces ER stress-mediated cytotoxic autophagy by increasing dihydroceramide levels in cancer cells.Autophagy · 2021Article
- Tumor progression locus 2 (TPL2) in tumor-promoting Inflammation, Tumorigenesis and Tumor Immunity.Theranostics · 2020Review
- Impact of ERK5 on the Hallmarks of Cancer.International journal of molecular sciences · 2019Review
- Participation of vitamin D-upregulated protein 1 (TXNIP)-ASK1-JNK1 signalosome in the enhancement of AML cell death by a post-cytotoxic differentiation regimen.The Journal of steroid biochemistry and molecular biology · 2019Article
- Silibinin: an old drug for hematological disorders.Oncotarget · 2017Review
- Nuclear ERK5 inhibits progression of leukemic monocytes to macrophages by regulating the transcription factor PU.1 and heat shock protein HSP70.Leukemia & lymphoma · 2017Article
- Established Human Cell Lines as Models to Study Anti-leukemic Effects of Flavonoids.Current genomics · 2017Article
- Enhancement of arabinocytosine (AraC) toxicity to AML cells by a differentiation agent combination.The Journal of steroid biochemistry and molecular biology · 2016Article
- Activator of G-protein Signaling 3 Controls Renal Epithelial Cell Survival and ERK5 Activation.Journal of molecular signaling · 2015Article
- Aberrant MEK5/ERK5 signalling contributes to human colon cancer progression via NF-κB activation.Cell death & disease · 2015Article
- 1,25-Dihydroxyvitamin D3 induces monocytic differentiation of human myeloid leukemia cells by regulating C/EBPβ expression through MEF2C.The Journal of steroid biochemistry and molecular biology · 2015Article
- The Potential of Vitamin D-Regulated Intracellular Signaling Pathways as Targets for Myeloid Leukemia Therapy.Journal of clinical medicine · 2015Review
- The MAPK ERK5, but not ERK1/2, inhibits the progression of monocytic phenotype to the functioning macrophage.Experimental cell research · 2015Article
- Novel Investigations of Flavonoids as Chemopreventive Agents for Hepatocellular Carcinoma.BioMed research international · 2015Review
- ERK 5/MAPK pathway has a major role in 1α,25-(OH)2 vitamin D3-induced terminal differentiation of myeloid leukemia cells.The Journal of steroid biochemistry and molecular biology · 2014Review
- ERK5 pathway regulates transcription factors important for monocytic differentiation of human myeloid leukemia cells.Journal of cellular physiology · 2014Article
- Role of cell cycle regulatory molecules in retinoic acid- and vitamin D3-induced differentiation of acute myeloid leukaemia cells.Cell proliferation · 2014Review
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6 authors at 4 institutions in 3 countries.
Funding
Abstract
Acute myelogenous leukemia (AML) is a disease characterized by dysregulated cell proliferation associated with impaired cell differentiation, and current treatment regimens rarely save the patient. Thus, new mechanism-based approaches are needed to improve prognosis of this disease. We have investigated in preclinical studies the potential anti-leukemia use of the plant-derived polyphenol Silibinin (SIL) in combination with 1,25-dihydroxyvitamin D3 (1,25D). Although most of the leukemic blasts ex vivo responded by differentiation to treatment with this combination, the reasons for the absence of SIL-1,25D synergy in some cases were unclear. Here we report that failure of SIL to enhance the action of 1,25D is likely due to the SIL-induced increase in the activity of differentiation-antagonizing cell components, such as ERK5. This kinase is under the control of Cot1/Tlp2, and inhibition of Cot1 activity by a specific pharmacological inhibitor 4-(3-chloro-4-fluorophenylamino)-6-(pyridin-3-yl-methylamino-3-cyano-[1-7]-naphthyridine, or by Cot1 siRNA, increases the differentiation by SIL/1,25D combinations. Conversely, over-expression of a Cot1 construct increases the cellular levels of P-ERK5, and SIL/1,25D-induced differentiation and cell cycle arrest are diminished. It appears that reduction in ERK5 activity by inhibition of Cot1 allows SIL to augment the expression of 1,25D-induced differentiation promoting factors and cell cycle regulators such as p27 (Kip1) , which leads to cell cycle arrest. This study shows that in some cell contexts SIL/1,25D can promote expression of both differentiation-promoting and differentiation-inhibiting genes, and that the latter can be neutralized by a highly specific pharmacological inhibitor, suggesting a potential for supplementing treatment of AML with this combination of agents.
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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 Socratic graph.