ArticleCancer science2016
Combination of panobinostat with ponatinib synergistically overcomes imatinib-resistant CML cells.
Article in Cancer science, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 37 citations in OpenAlex.
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- Martinostat as a novel HDAC inhibitor to overcome tyrosine kinase inhibitor resistance in chronic myeloid leukemia.Clinical epigenetics · 2025Article
- HDAC inhibitor chidamide overcomes drug resistance in chronic myeloid leukemia with the T315i mutation through the Akt-autophagy pathway.Human cell · 2023Article
- Chronic myeloid leukemia stem cells: targeting therapeutic implications.Stem cell research & therapy · 2021Review
- Characterization of newly established Pralatrexate-resistant cell lines and the mechanisms of resistance.BMC cancer · 2021Article
- Clinical epigenetics settings for cancer and cardiovascular diseases: real-life applications of network medicine at the bedside.Clinical epigenetics · 2021Review
- Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms.International journal of molecular sciences · 2021Review
- Review
- A Review on the Therapeutic Role of TKIs in Case of CML in Combination With Epigenetic Drugs.Frontiers in genetics · 2021Review
- Expanding the Structural Diversity of DNA Methyltransferase Inhibitors.Pharmaceuticals (Basel, Switzerland) · 2020Article
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- Venetoclax and alvocidib are both cytotoxic to acute myeloid leukemia cells resistant to cytarabine and clofarabine.BMC cancer · 2020Article
- Role of HDACs in normal and malignant hematopoiesis.Molecular cancer · 2020Review
- Article
- HDAC1,2 Knock-Out and HDACi Induced Cell Apoptosis in Imatinib-Resistant K562 Cells.International journal of molecular sciences · 2019Article
- Sodium butyrate and panobinostat induce apoptosis of chronic myeloid leukemia cells via multiple pathways.Molecular genetics & genomic medicine · 2019Article
- Management of Chronic Myeloid Leukemia in Advanced Phase.Frontiers in oncology · 2019Review
- Non ABL-directed inhibitors as alternative treatment strategies for chronic myeloid leukemia.Molecular cancer · 2018Review
- Association of Smoking, Alcohol Use, and Betel Quid Chewing with Epigenetic Aberrations in Cancers.International journal of molecular sciences · 2017Review
- Combination of panobinostat with ponatinib synergistically overcomes imatinib-resistant CML cells.Cancer science · 2016Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The major mechanism of imatinib (IM) resistance of CML is the reactivation of ABL kinase either through BCR-ABL gene amplification or mutation. We investigated the cytotoxicity of a pan-ABL tyrosine kinase inhibitor, ponatinib, and a pan-histone deacetylase inhibitor, panobinostat, against IM-resistant CML cells in vitro. Two different IM-resistant cell lines, K562/IM-R1 and Ba/F3/T315I were evaluated in comparison with their respective, parental cell lines, K562 and Ba/F3. K562/IM-R1 overexpressed BCR-ABL due to gene amplification. Ba/F3/T315I was transfected with a BCR-ABL gene encoding T315I-mutated BCR-ABL. Ponatinib inhibited the growth of both K562/IM-R1 and Ba/F3/T315I as potently as it inhibited their parental cells with an IC50 of 2-30 nM. Panobinostat also similarly inhibited the growth of all of the cell lines with an IC50 of 40-51 nM. This was accompanied by reduced histone deacetylase activity, induced histone H3 acetylation, and an increased protein level of heat shock protein 70, which suggested disruption of heat shock protein 90 chaperone function for BCR-ABL and its degradation. Importantly, the combination of ponatinib with panobinostat showed synergistic growth inhibition and induced a higher level of apoptosis than the sum of the apoptosis induced by each agent alone in all of the cell lines. Ponatinib inhibited phosphorylation not only of BCR-ABL but also of downstream signal transducer and activator of transcription 5, protein kinase B, and ERK1/2 in both K562/IM-R1 and Ba/F3/T315I, and the addition of panobinostat to ponatinib further inhibited these phosphorylations. In conclusion, panobinostat enhanced the cytotoxicity of ponatinib towards IM-resistant CML cells including those with T315I-mutated BCR-ABL.
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