ArticleCancer science2012
Romidepsin (FK228) and its analogs directly inhibit phosphatidylinositol 3-kinase activity and potently induce apoptosis as histone deacetylase/phosphatidylinositol 3-kinase dual inhibitors.
Article in Cancer science, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 54 citations in OpenAlex.
- Cellular senescence and aging: molecular mechanisms and convergent pathways.Cellular and molecular life sciences : CMLS · 2026Review
- The effect of combining HIV latency reversal with inhibition of phosphoinositide-3 kinases or B-cell lymphoma-2 on the HIV reservoir.PLoS pathogens · 2026Article
- Article
- Computer-aided Drug Discovery of Epigenetic Modulators in Dual-target Therapy of Multifactorial Diseases.Current topics in medicinal chemistry · 2025Review
- FK228 suppress the growth of human malignant pleural mesothelioma tumor independent to epithelioid or non-epithelioid histology.Molecular medicine (Cambridge, Mass.) · 2024Article
- The Role of the Unbinding Cycle on the Coordination Abilities of the Bi-Cyclopeptides toward Cu(II) Ions.Molecules (Basel, Switzerland) · 2024Article
- Emerging Role of Epigenetic Modifiers in Breast Cancer Pathogenesis and Therapeutic Response.Cancers · 2023Review
- Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma.Journal of experimental & clinical cancer research : CR · 2021Article
- FK228 sensitizes radioresistant small cell lung cancer cells to radiation.Clinical epigenetics · 2021Article
- LPIN1 downregulation enhances anticancer activity of the novel HDAC/PI3K dual inhibitor FK-A11.Cancer science · 2021Article
- Mechanistic differences underlying HIV latency in the gut and blood contribute to differential responses to latency-reversing agents.AIDS (London, England) · 2020Article
- Histone Deacetylase Inhibitors as Multitarget-Directed Epi-Drugs in Blocking PI3K Oncogenic Signaling: A Polypharmacology Approach.International journal of molecular sciences · 2020Review
- Using Chemical Epigenetics to Target Cancer.Molecular cell · 2020Review
- Selenium protects against cadmium-induced kidney apoptosis in chickens by activating the PI3K/AKT/Bcl-2 signaling pathway.Environmental science and pollution research international · 2017Article
- Antitumor activity and pharmacologic characterization of the depsipeptide analog as a novel histone deacetylase/ phosphatidylinositol 3-kinase dual inhibitor.Cancer science · 2017Article
- HDACs and HDAC Inhibitors in Cancer Development and Therapy.Cold Spring Harbor perspectives in medicine · 2016Review
- Romidepsin enhances the cytotoxicity of fludarabine, clofarabine and busulfan combination in malignant T-cells.Leukemia research · 2016Article
- HDAC Inhibitors as Epigenetic Regulators of the Immune System: Impacts on Cancer Therapy and Inflammatory Diseases.BioMed research international · 2016Review
- Romidepsin targets multiple survival signaling pathways in malignant T cells.Blood cancer journal · 2015Article
- Histone Modifications, Modifiers and Readers in Melanoma Resistance to Targeted and Immune Therapy.Cancers · 2015Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Activation of phosphatidylinositol 3-kinase (PI3K) signaling is involved in carcinogenesis and cancer progression. The PI3K inhibitors are considered candidate drugs for cancer treatment. Here, we describe a drug screening system for novel PI3K inhibitors using Saccharomyces cerevisiae strains with deleterious mutations in the ATP-binding cassette transporter genes, because wild-type S. cerevisiae uses drug efflux pumps for reducing intracellular drug concentrations. By screening the chemical library of the Screening Committee of Anticancer Drugs, we identified the histone deacetylase (HDAC) inhibitor romidepsin (FK228) and its novel analogs. In vitro PI3K activity assays confirmed that these compounds directly inhibit PI3K activity at μM-range concentrations. FK-A5 analog was the most potent inhibitor. Western blotting revealed that these compounds inhibit phosphorylation of protein kinase B and downstream signaling components. Molecular modeling of the PI3K-FK228 complex indicated that FK228 binds to the ATP-binding pocket of PI3K. At μM-range concentrations, FK228 and FK-A5 show potent cytotoxicity, inducing apoptosis even in HDAC inhibitor-resistant cells. Furthermore, HDAC/PI3K dual inhibition by FK228 and FK-A5 at μM-range concentrations potentiates the apoptosis induction, mimicking the effect of combining specific HDAC and PI3K inhibitors. In this study, we showed that FK228 and its analogs directly inhibit PI3K activity and induce apoptosis at μM-range concentrations, similar to HDAC/PI3K dual inhibition. In future, optimizing the potency of FK228 and its analogs against PI3K may contribute to the development of novel HDAC/PI3K dual inhibitors for cancer treatment.
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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.