Researcher:
Bulut, İpek

Profile Picture
ORCID

Job Title

PhD Student

First Name

İpek

Last Name

Bulut

Name

Name Variants

Bulut, İpek

Email Address

Birth Date

Filters

2021 - 20223

Advanced Search

Filter by

Settings

Researcher Of Publications: search.filters.isAuthorOfPublication.571a6a48-2610-449c-aecc-ab01ca5bdfbb

Search Results

Now showing 1 - 3 of 3
  • Placeholder
    PublicationMetadata only
    Dual LSD1 and HDAC6 inhibition induces doxorubicin sensitivity in acute Myeloid Leukemia cells
    (MDPI, 2022) Lee, Adam; Cevatemre, Buse; Ruzic, Dusan; Belle, Roman; Kawamura, Akane; Gul, Sheraz; Nikolic, Katarina; Ganesan, A.; Acilan, Ceyda; Bulut, İpek; PhD Student; Graduate School of Health Sciences; N/A
    Simple Summary GSK2879552 is a LSD1 inhibitor in clinical development. By structural modification, we obtained an analogue that is a potent and selective dual inhibitor of HDAC6 and LSD1 (IC50 110 and 540 nM, respectively). The dual targeting agent was superior to GSK2879552 in the growth inhibition of two acute myeloid leukemia (AML) cell lines. In combination experiments, the dual inhibitor primed AML cells to apoptosis with a sublethal concentration of doxorubicin. Our data suggest that doxorubicin toxicity can be reduced by parallel inhibition of HDAC6 and LSD1. Defects in epigenetic pathways are key drivers of oncogenic cell proliferation. We developed a LSD1/HDAC6 multitargeting inhibitor (iDual), a hydroxamic acid analogue of the clinical candidate LSD1 inhibitor GSK2879552. iDual inhibits both targets with IC50 values of 540, 110, and 290 nM, respectively, against LSD1, HDAC6, and HDAC8. We compared its activity to structurally similar control probes that act by HDAC or LSD1 inhibition alone, as well as an inactive null compound. iDual inhibited the growth of leukemia cell lines at a higher level than GSK2879552 with micromolar IC50 values. Dual engagement with LSD1 and HDAC6 was supported by dose dependent increases in substrate levels, biomarkers, and cellular thermal shift assay. Both histone methylation and acetylation of tubulin were increased, while acetylated histone levels were only mildly affected, indicating selectivity for HDAC6. Downstream gene expression (CD11b, CD86, p21) was also elevated in response to iDual treatment. Remarkably, iDual synergized with doxorubicin, triggering significant levels of apoptosis with a sublethal concentration of the drug. While mechanistic studies did not reveal changes in DNA repair or drug efflux pathways, the expression of AGPAT9, ALOX5, BTG1, HIPK2, IFI44L, and LRP1, previously implicated in doxorubicin sensitivity, was significantly elevated.
  • Thumbnail Image
    PublicationOpen Access
    Solution chemical properties and anticancer potential of 8-hydroxyquino-line hydrazones and their oxidovanadium(IV) complexes
    (Elsevier, 2022) Ribeiro, Nadia; Posa, Vivien; Sciortino, Giuseppe; Pessoa, Joao Costa; Maia, Luisa B.; Ugone, Valeria; Garribba, Eugenio; Enyedy, Eva A.; Correia, Isabel; Bulut, İpek; Sergi, Barış; Ayhan, Ceyda Açılan; Master Student; PhD Student; PhD Student; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Health Sciences; School of Medicine; N/A; N/A; 219658
    We report the synthesis and characterization of a family of benzohydrazones (L-n, n = 1-6) derived from 2-car-baldehyde-8-hydroxyquinoline and benzylhydrazides containing different substituents in the para position. Their oxidovanadium(IV) complexes were prepared and compounds with 1:1 and 1:2 metal-to-ligand stoichiometry were obtained. All compounds were characterized by elemental analyses and mass spectrometry as well as FTIR, UV-visible absorption, NMR (ligand precursors) and EPR (complexes) spectroscopies, and by DFT computational methods. Proton dissociation constants, lipophilicity and solubility in aqueous media were determined for all ligand precursors. Complex formation with V(IV)O was evaluated by spectrophotometry for L-4 (Me-substituted) and L-6 (OH-substituted) and formation constants for mono [VO(HL)](+), [VO(L)] and bis [VO(HL)(2)], [VO(HL) (L)], [VO(L)(2)](2- )complexes were determined. EPR spectroscopy indicates the formation of [VO(HL)](+) and [VO (HL)(2)], with this latter being the major species at the physiological pH. Noteworthy, the EPR data suggest a different behaviour for L-4 and L-6, which confirm the results obtained in the solid state. The antiproliferative activity of all compounds was evaluated in malignant melanoma (A-375) and lung (A-549) cancer cells. All complexes show much higher activity on A-375 (IC50 < 6.3 mu M) than in A-549 cells (IC50 > 20 mu M). Complex 3 (F-substituted) shows the lowest IC50 on both cell lines and lower than cisplatin (in A-375). Studies identified this compound as the one showing the highest increase in Annexin-V staining, caspase activity and induction of double stranded breaks, corroborating the cytotoxicity results. The mechanism of action of the complexes involves reactive oxygen species (ROS) induced DNA damage, and cell death by apoptosis.
  • Thumbnail Image
    PublicationOpen Access
    Understanding the potential in vitro modes of action of bis(beta-diketonato) oxovanadium(IV) complexes
    (Wiley, 2021) Xia, Ying; Waller, Zoe A. E.; Yıldızhan Yasemin; Lord, Rianne M.; Sergi, Barış; Bulut, İpek; Ayhan, Ceyda Açılan; PhD Student; Master Student; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Health Sciences; School of Medicine; N/A; N/A; 219658
    To understand the potential in vitro modes of action of bis(beta-diketonato) oxovanadium(IV) complexes, nine compounds of varying functionality have been screened using a range of biological techniques. The antiproliferative activity against a range of cancerous and normal cell lines has been determined, and show these complexes are particularly sensitive against the lung carcinoma cell line, A549. Annexin V (apoptosis) and Caspase-3/7 assays were studied to confirm these complexes induce programmed cell death. While gel electrophoresis was used to determine DNA cleavage activity and production of reactive oxygen species (ROS), the Comet assay was used to determine induced genomic DNA damage. Additionally, Forster resonance energy transfer (FRET)-based DNA melting and fluorescent intercalation displacement assays have been used to determine the interaction of the complexes with double strand (DS) DNA and to establish preferential DNA base-pair binding (AT versus GC).