Biology subjects

Kahraman, D. C.

Publications and source records attributed to Kahraman, D. C..

3 recordsLinked to original sources

bioRxiv2024

SYNERGISTIC ANTITUMOR EFFECT OF NAPROXEN AND SORAFENIB IN HEPATOCELLULAR CARCINOMA

Hepatocellular carcinoma (HCC) is one of the most prevalent and deadliest cancer types in the world. Due to the inevitable development of resistance to classical chemotherapy and current targeted therapies, combination therapy became an important strategy. Recently drug repurposing studies have emphasized the potential of non-steroidal anti-inflammatory drugs (NSAIDs) in exhibiting anti-tumor activities in different cancer types, including HCC. In this study we explored the synergistic bioactivity of naproxen in combination with sorafenib in HCC cell lines. Network reconstruction analysis, performed to identify key factors mediating the synergistic therapeutic effects of sorafenib and naproxen revealed apoptosis pathways enriched in both sorafenib and naproxen networks. CAPN2 emerged as the common gene shared between the two networks. In vitro studies on Huh7 and Mahlavu cells revealed that induction of apoptosis was associated mainly with the PI3K/AKT pathway inhibition. Furthermore, combined treatment of naproxen and sorafenib led to the downregulation of CAPN2 expression, suggesting a potential link to apoptosis and PI3K/AKT pathway regulation, which needs further investigation. In conclusion, combining sorafenib with naproxen presents a promising strategy with potential synergistic therapeutic benefits in HCC.

cancer biology↗

bioRxiv2021

Context dependent isoform specific PI3K inhibition confers drugresistance in Hepatocellular carcinoma cells

BackgroundTargeted therapies for Primary liver cancer (HCC) is limited to the multi-kinase inhibitors, and not fully effective due to the resistance to these agents because of the heterogeneous molecular nature of HCC developed during chronic liver disease stages and cirrhosis. Although combinatorial therapy can increase the efficiency of targeted therapies through synergistic activities, isoform specific effects of the inhibitors are usually ignored. This study concentrated on PI3K/Akt/mTOR pathway and the differential combinatory bioactivities of isoform specific PI3K- inhibitor (PIK-75) or PI3K-{beta} inhibitor (TGX-221) with Sorafenib dependent on PTEN context. MethodsThe bioactivities of inhibitors on PTEN adequate Huh7 and deficient Mahlavu cells were investigated with real time cell growth, cell cycle and cell migration assays. Differentially expressed genes from RNA-Seq were identified by edgeR tool. Systems level network analysis of treatment specific pathways were performed with Prize Collecting Steiner Tree (PCST) on human interactome and enriched networks were visualized with Cytoscape platform. ResultsOur data from combinatory treatment of Sorafenib and PIK-75 and TGX-221 showed opposite effects; while PIK-75 displays synergistic effects on Huh7 cells leading to apoptotic cell death, Sorafenib with TGX-221 display antagonistic effects and significantly promotes cell growth in PTEN deficient Mahlavu cells. Transcriptomic states of combinatory treatments with PIK-75 and TGX-221 inhibitors were identified in PTEN deficient and adequate cells. Molecular interactions and cell signaling pathways were reconstructed and analyzed in-depth to understand mechanism of differential synergistic or antagonistic effects of PI3K- (PIK-75) and PI3K-{beta} (TGX-221) inhibitors with Sorafenib. ConclusionsSimultaneously constructed and analyzed differentially expressed cellular networks presented in this study, revealed distinct consequences of isoform specific PI3K inhibition in PTEN adequate and deficient liver cancer cells. We demonstrated the importance of context dependent and isoform specific PI3K/Akt/mTOR signaling inhibition in drug resistance during combination therapies. (https://github.com/cansyl/Isoform-spesific-PI3K-inhibitor-analysis).

cancer biology↗

bioRxiv2018

Differential alteration of IL-8 in liver cancer stem cell enrichment in response to PI3K/Akt/mTOR inhibitors and sorafenib

Liver cancer stem cells (LCSCs) are derived from damaged and transformed Hepatic progenitor cells (HPCs) during precancerous cirrhosis stage. Ras/Raf/MAPK and PI3K/AKT/mTOR signaling pathways are significantly deregulated in liver cancer. The activation of PI3K/AKT/mTOR pathway in LCSC population is one of the reasons for acquired resistance to Sorafenib in advanced Hepatocellular carcinoma (HCC) patients. Therefore, identifying novel inhibitors targeting this pathway acting on LCSCs is highly essential. We therefore elucidated the bioactivities of small molecule kinase inhibitors on LCSCs acting through PI3K/Akt/mTOR pathway in comparison with DAPT (CSC inhibitor), DNA intercalators and Sorafenib. For this purpose, CD133+/EpCAM+ cells originated from HCC cells were analyzed by flow cytometry and effective inhibitors on LCSCs were further tested for their potential combinatorial effects. Treatment of cells with Sorafenib, and DNA intercalators resulted in enrichment of CD133+/EpCAM+ cells. Yet, mTOR inhibitor Rapamycin, and Notch pathway inhibitor DAPT significantly reduced CD133/EpCAM positivity. Combination studies revealed that sequential treatment strategy, which involves treatment of cells with Rapamycin prior to Sorafenib treatment, decreased the ratio of LCSCs as opposed to Sorafenib treatment alone or Sorafenib treatment prior to Rapamycin. The effect of the inhibitors were also demonstrated with LCSC sphere formation. Additionaly, a large panel of genes involved in cancer pathways were analyzed using Nanostring(R) nCounter(R) Technology to identify the differentially expressed genes in Rapamycin, Sorafenib or DAPT treated cells. Pathways involved in stemness (Wnt and Notch pathways) were differentially regulated between Rapamycin or DAPT treated cells and Sorafenib treated cells. Interleukin 8 (IL-8), FLNC, FLNA expressions were down-regulated upon treatment with DAPT or Rapamycin, yet up-regulated upon Sorafenib treatment. Following IL-8 inhibition CD133/EpCAM positivity of cells decreased significantly, indicating that IL-8 signaling is crucial for the conservation of stemness features of cancer cells.\n\nConclusionPI3K/Akt/mTOR pathway inhibitors alter hepatic CSC composition and gene expression in favor or to the detriment of cancer stem cell survival. Blockade of IL-8 signaling provides a promising therapeutic approach for prevention of LCSC enrichment.

cancer biology↗