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Through these effectors, IGFs mediate cell cycle progression, cancer cell proliferation and protection from apoptosis. Many cancers show aberrant signalling via the insulin-like growth factor (IGF) axis, activating type 1 IGF receptors (IGF-1Rs) and variant insulin receptors (INSRs) to signal via phosphatidylinositol 3-kinase–AKT–mammalian target of rapamycin (PI3K-AKT-mTOR) and mitogen-activated protein kinase kinase–extracellular signal-regulated kinases (MEK-ERK).
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These data identify novel therapeutic vulnerabilities and may inform future trials of IGF inhibitory drugs. Exogenous RRM2 expression rescued hallmarks of replication stress induced by co-inhibiting IGF with CHK1 or WEE1, identifying RRM2 as a critical target of the functional IGF:CHK1 and IGF:WEE1 interactions. Similar phenotypes were induced by IGF:WEE1 co-inhibition, also via exacerbation of RRM2 downregulation. These effects resulted in significant accumulation of unreplicated single-stranded DNA and increased cell death, indicative of replication catastrophe. Investigating the mechanism of synthetic lethality, we reveal that CHK1 inhibition in IGF-1R depleted or inhibited cells further downregulated RRM2, reduced dNTP supply and profoundly delayed replication fork progression. Co-inhibition of IGF and CHK1 caused synergistic suppression of cell viability, cell survival and tumour growth in 2D cell culture, 3D spheroid cultures and in vivo. Inhibitor of checkpoint kinase CHK1 was identified as a top screen hit. Aiming to exploit this effect in therapy we performed a compound screen in five breast cancer cell lines with IGF neutralising antibody xentuzumab. Department of Biochemistry, School of Medicine/Genetic and Metabolic Diseases Research and Investigation Center, Marmara University, Istanbul,TurkeyWe recently reported that genetic or pharmacological inhibition of insulin-like growth factor receptor (IGF-1R) slows DNA replication and induces replication stress by downregulating the regulatory subunit RRM2 of ribonucleotide reductase, perturbing deoxynucleotide triphosphate (dNTP) supply.Altundağ*, Kübra Toprak, Gizem Şanlıtürk, Mümtaz Güran, Cahit Özbilenler, Namık R. Title:Synergistic Combination of Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid and Natural Flavonoid Curcumin Exhibits Anticancer and Antibacterial ActivityĪuthor(s): Ergül M. Keywords: B-CPAP cells, SAHA, curcumin, apoptosis, anti-microbial activity, histone deacetylase inhibitor. aureus.Ĭonclusion: In the present study, synergistic combinations of SAHA and curcumin were shown to have bothĪnti-cancer and antibacterial activities that would provide a novel thyroid cancer treatment strategy.
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Curcumin was found to have better anti-microbialĪctivity than SAHA as having a lower MIC value, and checkerboard synergy analysis revealed that the twoĬompounds co-operate synergistically for the in vitro killing of S. WAF1 and P27/KIP1 protein expressions were upregulated. Increase in the percentage of B-CPAP cells in the S-phase due to cell arrest. Combination treatment showed a significant Using half of the dose required for SAHA and curcumin alone. The apoptotic effect was achieved by combination treatment (51.85%) on B-CPAP cells The combination index CI value was determined as 0.891 in B-CPAP cells, which demonstrate Results: Based on MTT assay, IC 50 values for SAHA and curcumin were determined as 0.91μM and 20.97μM, Broth microdilutionĪssay was performed to determine Minimum Inhibitory Concentration (MIC) values against S. Proteins (PARP, P21/CDKN1A/WAF1, P27/KIP1) were examined by western blot analysis. Expressions of apoptotic and cell cyclerelated Synergistic interactions between two agents were analyzed by Calcusyn software.Īpoptosis and cell cycle assays were measured by flow cytometry. Methods: MTT assay was used to determine the cell viability of B-CPAP cells upon treatment with SAHA,Ĭurcumin and their combinations. (SAHA) to increase both bioavailability of curcumin and the efficiency of SAHA, which have limited efficiency In this study,Ī novel combination strategy was applied by combining curcumin with Suberoylanilide Hydroxamic Acid However, its use in clinical applications is limited due to low solubility and bioavailability. Background and Objective: Curcumin is an effective anti-cancer agent used in thyroid cancer treatments.