Publications by authors named "Deniz Cansen Kahraman"

10 Publications

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Synthesis and biological evaluation of novel isoxazole-piperazine hybrids as potential anti-cancer agents with inhibitory effect on liver cancer stem cells.

Eur J Med Chem 2021 Oct 24;221:113489. Epub 2021 Apr 24.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey. Electronic address:

In our effort for the development of novel anticancer therapeutics, a series of isoxazole-piperazine analogues were prepared, and primarily screened for their antiproliferative potential against hepatocellular carcinoma (HCC; Huh7/Mahlavu) and breast (MCF-7) cancer cells. All compounds demonstrated potent to moderate cytotoxicity on all cell lines with IC values in the range of 0.09-11.7 μM. Further biological studies with 6a and 13d in HCC cells have shown that both compounds induced G1 or G2/M arrests resulting in apoptotic cell death. Subsequent analysis of proteins involved in cell cycle progression as well as proliferation of HCC cells revealed that 6a and 13d may affect cellular survival pathways differently depending on the mutation profiles of cells (p53 and PTEN), epidermal/mesenchymal characteristics, and activation of cell mechanisms through p53 dependent/independent pathways. Lastly, we have demonstrated the potential anti-stemness properties of these compounds in which the proportion of liver CSCs in Huh7 cells (CD133+/EpCAM+) were significantly reduced by 6a and 13d. Furthermore, both compounds caused a significant reduction in expression of stemness markers, NANOG or OCT4 proteins, in Mahlavu and Huh7 cells, as well as resulted in a decreased sphere formation capacity in Huh7 cells. Together, these novel isoxazole-piperazine derivatives may possess potential as leads for development of effective anti-cancer drugs against HCC cells with stem cell-like properties.
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http://dx.doi.org/10.1016/j.ejmech.2021.113489DOI Listing
October 2021

Transcriptome profiles associated with selenium-deficiency-dependent oxidative stress identify potential diagnostic and therapeutic targets in liver cancer cells.

Turk J Biol 2021 20;45(2):149-161. Epub 2021 Apr 20.

Cancer Systems Biology Laboratory, Department of Health Informatics, Graduate School of Informatics, Middle East Technical University, Ankara Turkey.

Hepatocellular carcinoma (HCC) is one of the most common cancer types with high mortality rates and displays increased resistance to various stress conditions such as oxidative stress. Conventional therapies have low efficacies due to resistance and off-target effects in HCC. Here we aimed to analyze oxidative stress-related gene expression profiles of HCC cells and identify genes that could be crucial for novel diagnostic and therapeutic strategies. To identify important genes that cause resistance to reactive oxygen species (ROS), a model of oxidative stress upon selenium (Se) deficiency was utilized. The results of transcriptome-wide gene expression data were analyzed in which the differentially expressed genes (DEGs) were identified between HCC cell lines that are either resistant or sensitive to Se-deficiency-dependent oxidative stress. These DEGs were further investigated for their importance in oxidative stress resistance by network analysis methods, and 27 genes were defined to have key roles; 16 of which were previously shown to have impact on liver cancer patient survival. These genes might have Se-deficiency-dependent roles in hepatocarcinogenesis and could be further exploited for their potentials as novel targets for diagnostic and therapeutic approaches.
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http://dx.doi.org/10.3906/biy-2009-56DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068766PMC
April 2021

Induction of Apoptosis in Hepatocellular Carcinoma Cell Lines by Novel Indolylacrylamide Derivatives: Synthesis and Biological Evaluation.

Chem Biodivers 2021 May 14;18(5):e2001037. Epub 2021 Apr 14.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330, Ankara, Turkey.

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and one of the leading causes of cancer associated death worldwide. This is due to the highly resistant nature of this malignancy and the lack of effective treatment options for advanced stage HCC patients. The hyperactivity of PI3K/Akt and Ras/Raf/MEK/ERK signaling pathways contribute to the cancer progression, survival, motility, and resistance mechanisms, and the interaction of these two pathways are responsible for the regulation of cancer cell growth and development. Therefore, it is vital to design and develop novel therapeutic options for HCC treatment targeting these hyperactive pathways. For this purpose, novel series of trans-indole-3-ylacrylamide derivatives originated from the lead compound, 3-(1H-indole-3-yl)-N-(3,4,5-trimethoxyphenyl)acrylamide, have been synthesized and analyzed for their bioactivity on cancer cells along with the lead compound. Based on the initial screening, the most potent compounds were selected to elucidate their effects on cellular signaling activity of HCC cell lines. Cell cycle analysis, immunofluorescence, and Western blot analysis revealed that lead compound and (E)-N-(4-tert-butylphenyl)-3-(1H-indole-3-yl)acrylamide induced cell cycle arrest at the G2/M phase, enhanced chromatin condensation and PARP-cleavage, addressing induction of apoptotic cell death. Additionally, these compounds decreased the activity of ERK signaling pathway, where phosphorylated ERK1/2 and c-Jun protein levels diminished significantly. Relevant to these findings, the lead compound was able to inhibit tubulin polymerization as well. To conclude, the novel trans-indole-3-ylacrylamide derivatives inhibit one of the critical pathways associated with HCC which results in cell cycle arrest and apoptosis in HCC cell lines.
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http://dx.doi.org/10.1002/cbdv.202001037DOI Listing
May 2021

Author Correction: CXXC5 as an unmethylated CpG dinucleotide binding protein contributes to estrogen-mediated cellular proliferation.

Sci Rep 2020 Jun 16;10(1):9943. Epub 2020 Jun 16.

Department of Biological Sciences, Middle East Technical University, Ankara, 06800, Turkey.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-66682-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297797PMC
June 2020

CXXC5 as an unmethylated CpG dinucleotide binding protein contributes to estrogen-mediated cellular proliferation.

Sci Rep 2020 04 6;10(1):5971. Epub 2020 Apr 6.

Department of Biological Sciences, Middle East Technical University, Ankara, 06800, Turkey.

Evidence suggests that the CXXC type zinc finger (ZF-CXXC) protein 5 (CXXC5) is a critical regulator/integrator of various signaling pathways that include the estrogen (E2)-estrogen receptor α (ERα). Due to its ZF-CXXC domain, CXXC5 is considered to be a member of the ZF-CXXC family, which binds to unmethylated CpG dinucleotides of DNA and through enzymatic activities for DNA methylation and/or chromatin modifications generates a chromatin state critical for gene expressions. Structural/functional features of CXXC5 remain largely unknown. CXXC5, suggested as transcription and/or epigenetic factor, participates in cellular proliferation, differentiation, and death. To explore the role of CXXC5 in E2-ERα mediated cellular events, we verified by generating a recombinant protein that CXXC5 is indeed an unmethylated CpG binder. We uncovered that CXXC5, although lacks a transcription activation/repression function, participates in E2-driven cellular proliferation by modulating the expression of distinct and mutual genes also regulated by E2. Furthermore, we found that the overexpression of CXXC5, which correlates with mRNA and protein levels of ERα, associates with poor prognosis in ER-positive breast cancer patients. Thus, CXXC5 as an unmethylated CpG binder contributes to E2-mediated gene expressions that result in the regulation of cellular proliferation and may contribute to ER-positive breast cancer progression.
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http://dx.doi.org/10.1038/s41598-020-62912-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136269PMC
April 2020

Targeting PI3K/Akt/mTOR Pathway Identifies Differential Expression and Functional Role of IL8 in Liver Cancer Stem Cell Enrichment.

Mol Cancer Ther 2019 11 22;18(11):2146-2157. Epub 2019 Aug 22.

Cancer Systems Biology Laboratory, Graduate School of Informatics, ODTU, Ankara, Turkey.

Activation of the PI3K/Akt/mTOR pathway is an important signaling mechanism involved in the development and the progression of liver cancer stem cell (LCSC) population during acquired Sorafenib resistance in advanced hepatocellular carcinoma (HCC). Therefore, identification of novel therapeutic targets involving this pathway and acting on LCSCs is highly essential. Here, we analyzed the bioactivities and the molecular pathways involved in the action of small-molecule PI3K/Akt/mTOR pathway inhibitors in comparison with Sorafenib, DNA intercalators, and DAPT (CSC inhibitor) on CD133/EpCAM-positive LCSCs. Sorafenib and DNA intercalators lead to the enrichment of LCSCs, whereas Rapamycin and DAPT significantly reduced CD133/EpCAM positivity. Sequential treatment with Rapamycin followed by Sorafenib decreased the ratio of LCSCs as well as their sphere formation capacity, as opposed to Sorafenib alone. Under the stress of the inhibitors, differential expression analysis of 770 cancer pathway genes using network-based systems biology approach singled out expression association with LCSCs. Furthermore, IL8 secretion and LCSC enrichment ratio was also positively correlated. Following IL8 inhibition with its receptor inhibitor Reparixin or siRNA knockdown, LCSC features of HCC cells were repressed, and sensitivity of cells to Sorafenib increased significantly. Furthermore, inflammatory cytokines (IL8, IL1β, and IL11) were also upregulated upon treatment with HCC-approved kinase inhibitors Sorafenib and Regorafenib. Hence, chemotherapeutic stress alters inflammatory cytokine gene expression in favor of hepatic CSC population survival. Autocrine IL8 signaling is identified as a critical event, and its inhibition provides a promising complimentary therapeutic approach for the prevention of LCSC population enrichment.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0004DOI Listing
November 2019

Synthesis, anticancer activity, toxicity evaluation and molecular docking studies of novel phenylaminopyrimidine-(thio)urea hybrids as potential kinase inhibitors.

Comput Biol Chem 2019 Feb 12;78:227-241. Epub 2018 Dec 12.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa, 34668 İstanbul, Turkey. Electronic address:

Thirty-two novel urea/thiourea compounds as potential kinase inhibitor were designed, synthesized and evaluated for their cytotoxic activity on breast (MCF7), colon (HCT116) and liver (Huh7) cancer cell lines. Compounds 10, 19 and 30 possessing anticancer activity with IC values of 0.9, 0.8 and 1.6μM respectively on Huh7 cells were selected for further studies. These hit compounds were tested against liver carcinoma panel. Real time cell electronic sensing assay was used to evaluate the effects of the compounds 10, 19 and 30 on the growth pattern of liver cancer cells. Apoptotic cell death and cell cycle analysis upon treatment of liver carcinoma cells with hit compounds were determined. A significant apoptotic cell death was detected upon treatment of Huh7 and Mahlavu cells with compound 30 after 48 h of treatment. Additionally, compound 10 caused cell cycle arrest at G0/G1 phase. Mutagenicity of hit compounds was evaluated. Assertively, these compounds were not found to be mutagenic on Salmonella typhimurium strains TA98 and TA100. To understand the binding modes of the synthesized compounds, molecular docking studies were performed using the crystal data of VEGFR and Src-kinase enzymes in correlation with anticancer activities.
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http://dx.doi.org/10.1016/j.compbiolchem.2018.12.003DOI Listing
February 2019

Design, synthesis and biological evaluation of novel 1,3-diarylpyrazoles as cyclooxygenase inhibitors, antiplatelet and anticancer agents.

Medchemcomm 2018 May 6;9(5):795-811. Epub 2018 Apr 6.

Division of Pharmaceutical Sciences , Department of Pharmaceutical Chemistry , Faculty of Pharmacy , Gazi University , 06330 , Ankara , Turkey . Email:

With the aim of achieving new compounds possessing both anti-inflammatory and antiplatelet activities, we synthesized ()-3-[3-(pyridin-3/4-yl)-1-(phenyl/sulfonylmethylphenyl)-1-pyrazol-4-yl]acrylamides, and evaluated their COX-1 and COX-2 inhibitory and antiplatelet activities. Since COX-2 inhibitory and antiplatelet compounds have anticancer potential, we also screened their antiproliferative effects against three human cancer cell lines. Compounds , , , , and were determined as dual COX-2 inhibitor/antiplatelet compounds. Compound appeared to be a compound that exhibited antiplatelet activity without inhibiting the COX enzyme. Compounds , and were the most effective derivatives which displayed antiproliferative activity against Huh7, MCF7 and HCT116 cells. Particularly, compound , as the compound exhibiting the highest cytotoxic, antiplatelet and COX-2 inhibitory activity, was remarkable.
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http://dx.doi.org/10.1039/c8md00022kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072348PMC
May 2018

Synthesis and biological evaluation of novel pyrazolic chalcone derivatives as novel hepatocellular carcinoma therapeutics.

Eur J Med Chem 2017 Mar 10;129:12-26. Epub 2017 Feb 10.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330, Ankara, Turkey. Electronic address:

Despite having the second highest mortality associated with cancer, currently Sorafenib is the only FDA-approved chemotherapeutic agent available for liver cancer patients which can only improve survival for few months. In this study, various pyrazolic chalcone analogous compounds were synthesized and evaluated as potential chemotherapeutic agents for the treatment of hepatocellular carcinoma (HCC). Modifying the central pyrazole ring at the C(3)-position with different heteroaryl rings and substituting the C(4)-position of pyrazole with differently substituted chalcone moiety produced fouthy two variant compounds. For all these compounds, cytotoxicity was evaluated using sulforhodamine B assay and real time cell growth tracking, respectively. Based on 50% inhibitory concentration (IC) values, compounds 39, 42, 49, and 52 were shown to exhibit potent cytotoxic activity against all the cancer cell lines tested, and had better cytotoxic activities than the well-known chemotherapeutic drug 5-FU. Therefore, these compounds were chosen to be further evaluated in a panel of HCC cell lines. Flow cytometric analysis of HCC cells treated with compounds 39, 42, 49, and 52 demonstrated that these compounds caused cell cycle arrest at G2/M phase followed by the apoptotic cell death and impaired cell growth as shown by real-time cell growth surveillance. Consistent with these results, western blotting of HCC cells treated with the compounds resulted in molecular changes for cell cycle proteins, where p21 levels were increased independent of p53 and the levels of the key initiators of mitosis Cyclin B1 and CDK1 were shown to decrease upon treatment. In conclusion, chalcone derivatives 42 and 52 show potent bioactivities by modulating the expression of cell-cycle related proteins and resulting in cell-cycle arrest in the HCC cell lines tested here, indicating that the compounds can be considered as preclinical candidates.
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http://dx.doi.org/10.1016/j.ejmech.2017.02.002DOI Listing
March 2017

Quinoides and VEGFR2 TKIs influence the fate of hepatocellular carcinoma and its cancer stem cells.

Medchemcomm 2017 Jan 7;8(1):81-87. Epub 2016 Oct 7.

Cancer Systems Biology Laboratory , Graduate School of Informatics , ODTU , Ankara , 06800 , Turkey . Email:

Bioactivities of quinoides and VEGFR2 TKIs in hepatocellular cancer (HCC) and cancer stem cells (HCSCs) were studied. The compounds exhibited IC values in μM concentrations in HCC cells. Quinoide was able to eradicate cancer stem cells, similar to the action of the stem cell inhibitor . However, the more cytotoxic VEFGR TKIs (IC: 0.4-3.0 μM) including sorafenib, which is the only FDA approved drug for the treatment of HCC, enriched the hepatocellular cancer stem cell population by 2-3 fold after treatment. An aggressiveness factor () was proposed to quantify the characteristics of drug candidates for their ability to eradicate the CSC subpopulation. Considering the tumour heterogeneity and marker positive cancer stem cell like subpopulation enrichment upon treatments in patients, this study emphasises the importance of the chemotherapeutic agent choice acting differentially on all the subpopulations including marker-positive CSCs.
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http://dx.doi.org/10.1039/c6md00392cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072489PMC
January 2017