scholarly journals Novel Pyridine Bioisostere of Cabozantinib as a Potent c-Met Kinase Inhibitor: Synthesis and Anti-Tumor Activity against Hepatocellular Carcinoma

2021 ◽  
Vol 22 (18) ◽  
pp. 9685
Author(s):  
Ujjwala Karmacharya ◽  
Diwakar Guragain ◽  
Prakash Chaudhary ◽  
Jun-Goo Jee ◽  
Jung-Ae Kim ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Proliferative Activity ◽  
Kinase Inhibitor ◽  
Tumor Model ◽  
Docking Study ◽  
Conformational Ensemble ◽  
H1299 Cell ◽  
Tumor Selectivity ◽  
Factor C

Two novel bioisosteres of cabozantinib, 3 and 4, were designed and synthesized. The benzene ring in the center of the cabozantinib structure was replaced by trimethylpyridine (3) and pyridine (4), respectively. Surprisingly, the two compounds showed extremely contrasting mesenchymal–epithelial transition factor (c-Met) inhibitory activities at 1 μM concentration (4% inhibition of 3 vs. 94% inhibition of 4). The IC50 value of compound 4 was 4.9 nM, similar to that of cabozantinib (5.4 nM). A ligand-based docking study suggested that 4 includes the preferred conformation for the binding to c-Met in the conformational ensemble, but 3 does not. The anti-proliferative activity of compound 4 against hepatocellular carcinoma (Hep3B and Huh7) and non-small-cell lung cancer (A549 and H1299) cell lines was better than that of cabozantinib, whereas 3 did not show a significant anti-proliferative activity. Moreover, the tumor selectivity of compound 4 toward hepatocellular carcinoma cell lines was higher than that of cabozantinib. In the xenograft chick tumor model, compound 4 inhibited Hep3B tumor growth to a much greater extent than cabozantinib. The present study suggests that compound 4 may be a good therapeutic candidate against hepatocellular carcinoma.

scholarly journals Molecular Imaging of Nonsmall Cell Lung Carcinomas Expressing Active Mutant EGFR Kinase Using PET with [124I]-Morpholino-IPQA

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Skye Hsin-Hsien Yeh ◽  
Chien-Feng Lin ◽  
Fan-Lin Kong ◽  
Hsin-Ell Wang ◽  
Ya-Ju Hsieh ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Water Solubility ◽  
Kinase Inhibitor ◽  
Control Cell ◽  
H1299 Cell ◽  
Subcutaneous Tumor ◽  
Tumor Xenografts ◽  
H1299 Cell Line

Mutations in the kinase domain of epidermal growth factor receptor (EGFR) have high levels of basal receptor phosphorylation and are associated with clinical responsiveness to Iressa in patients with nonsmall cell lung cancer (NSCLC). This study aimed to assess the feasibility of morpholino-[124I]IPQA derivative as anin vivoPET imaging tool for the expression of different EGFR mutants in NSCLC.In vitroradiotracer accumulation and washout studies demonstrated a rapid accumulation and progressive retention after washout of morpholino-[131I]IPQA derivative in high EGFR-expressing H1299 NSCLC derivative cell lines (L858R and E746-A750 del cell lines), but not in EGFR-transfected H1299 cell line and vector-transfected H1299 cell line. Using the morpholino-[124I]IPQA derivative, we obtained noninvasive microPET images of EGFR activity in L858R and E746-A750 del subcutaneous tumor xenografts, but not in subcutaneous tumor xenografts grown form control cell line. Different EGFR mutant (activity) tumors have a different morpholino-[∗I]IPQA derivative uptake. However, it still needs to modify the structure of IPQA to increase its water solubility and reduce hepatobiliary clearance. Morpholino-[124I]IPQA derivative may be a potential probe for selection of the candidate patients suffering from NSCLC for the small molecule tyrosine kinase inhibitor therapy (e.g., Iressa) in the future.

scholarly journals Sorafenib fails to trigger ferroptosis across a wide range of cancer cell lines

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Jiashuo Zheng ◽  
Mami Sato ◽  
Eikan Mishima ◽  
Hideyo Sato ◽  
Bettina Proneth ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Renal Cell Carcinoma ◽  
Cell Death ◽  
Tumor Cell ◽  
Cell Lines ◽  
Kinase Inhibitor ◽  
Genetically Engineered ◽  
Tumor Cell Lines ◽  
Wide Range ◽  
Bona Fide

AbstractSorafenib, a protein kinase inhibitor approved for the treatment of hepatocellular carcinoma and advanced renal cell carcinoma, has been repeatedly reported to induce ferroptosis by possibly involving inhibition of the cystine/glutamate antiporter, known as system xc−. Using a combination of well-defined genetically engineered tumor cell lines and canonical small molecule ferroptosis inhibitors, we now provide unequivocal evidence that sorafenib does not induce ferroptosis in a series of tumor cell lines unlike the cognate system xc− inhibitors sulfasalazine and erastin. We further show that only a subset of tumor cells dies by ferroptosis upon sulfasalazine and erastin treatment, implying that certain cell lines appear to be resistant to system xc− inhibition, while others undergo ferroptosis-independent cell death. From these findings, we conclude that sorafenib does not qualify as a bona fide ferroptosis inducer and that ferroptosis induced by system xc− inhibitors can only be achieved in a fraction of tumor cell lines despite robust expression of SLC7A11, the substrate-specific subunit of system xc−.

Evaluation of the Consequence of CTNNB1 & RAB1A Targeting on Hepatocellular Carcinoma Cell Line

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Amira Salah Ismail ◽  
Samar Kamal Kassim ◽  
Hanan H Shehata ◽  
Magda I Mohamad ◽  
Marian Maher Salib Roushdy
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Liver Cancer ◽  
Hepg2 Cell ◽  
Cell Lines ◽  
Hepg2 Cells ◽  
Proliferative Activity ◽  
Trypan Blue ◽  
Liver Tumors ◽  
Hepg2 Cell Lines

Abstract Background Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and the most common cause of death in people with chronic liver diseases. In Egypt, liver cancer forms 11.75% of the malignancies of all digestive organs and 1.68% of the total malignancies. HCC constitutes 70.48% of all liver tumors among Egyptians. In the past few years, early diagnosis and advances in therapeutic measures have greatly improved the outcome of HCC patients. However, the prognosis is still poor with overall survival rates of 3-5%. The alterations in cancer driver genes and associated pathways are the major triggers for HCC. So, the identification and targeting of these genes are beneficial to understand HCC and to develop a new therapy. Aim of the work We aimed to target CTNNB1 and RAB1A oncogenes in HepG2 cell lines by RNAi then evaluate the effect of their targeting on the viability and proliferative activity of HepG2 cells. Materials and methods Using HepG2 cell lines, CTNNB1 & RAB1A oncogenes were targeted using two different siRNAs (small interfering RNA) for each gene. The viability of HepG2 was conducted by Trypan blue test. The cell proliferation was tested by CellTiter 96® AQueous One Solution Cell Proliferation Assay. Results There was significant reduction in the cells’ viability detected by trypan blue test in transfected cells with siRNA targeting either CTNNB1 or RAB1A compared to Mock HepG2 cell lines (p <0.05). In addition, the proliferative activity was significantly lower in both HepG2 cell lines transfected with siRNA targeting the previous genes compared to mock cells (p < 0.05). Furthermore, HepG2 cells transfected with siRNA targeting RAB1A were more proliferative compared to those transfected with siRNA targeting CTNNB1 (p <0.05). Conclusion Targeting CTNNB1or RAB1A in HepG2 cell lines decreased the cell viability and proliferative activity. Moreover, targeting CTNNB1 was effective in decreasing cell proliferative activity compared to targeting RAB1A in HepG2 cell lines. So, targeting CTNNB1 may have a potential therapeutic effect in treatment of HCC.

Selective Abrogation of STAT5 Expression Impairs the Proliferation of Acute Myeloid Leukemia Cells with Various Cytogenetic Alterations

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5024-5024
Author(s):  
Youngsoo Kim ◽  
Tianyuan Zhou ◽  
Shuling Guo ◽  
Andy Siwkowski ◽  
Donna Witchell ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Proliferative Activity ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Significant Inhibition ◽  
Acute Myeloid

Abstract STAT5 is a key common downstream mediator of multiple signaling pathways which are often dysregulated in various hematologic malignancies, including acute myeloid leukemia (AML). Due to the heterogeneity and high relapse rate of the disease, the treatment options for AML are currently limited. Although the approach of treating the disease by inhibiting upstream kinases such as FLT3 within these signaling pathways appeared promising, the clinical efficacy of these drugs as mono-therapy have been disappointing. We hypothesized that this lack of efficacy might be due to the residual STAT5 activity that is present even in the presence of these inhibitors in vivo. Therefore, abrogating the expression of the final regulator of these pathways, STAT5, might be a much more efficient way of blocking signaling, thus inhibiting the proliferation and survival of AML cells. In this study, we first investigated the role of STAT5 in the proliferation of AML cells by selectively suppressing the expression of the gene using 2nd-Generation antisense oligonucleotides (ASOs). Suppression of STAT5 following ASO treatment (>80% over control ASO) led to a significant inhibition of cell proliferation (50~70% over control ASO), a decrease in colony formation, and a modest induction of apoptosis in a range of AML lines including KG-1α, MV-4-11, and MOLM-13. STAT5 ASO treatment was highly specific for the STAT5 target and produced predictable effects on gene expression, as demonstrated by the downregulation of Pim-1 and cyclin D1, well-known STAT5 regulated genes. No changes in the expression levels of Bcl-XL, STAT1, and STAT3 were observed. Furthermore, relative anti-proliferative activity within the various AML lines correlated well with the relative levels of STAT5 activity. Interestingly, there was a strong correlation between the extent of STAT5/Pim-1 downregulation and the degree of anti-proliferation, suggesting a possible role of Pim-1 as a downstream effector of STAT5 ASO anti-proliferative activity. Studies comparing the relative effects of the STAT5 ASO inhibitor with the potent multi kinase inhibitor CEP701 in various AML cell lines demonstrated potent anti-proliferative activity for the STAT5 inhibitor in the cell lines including KG-1α that display resistance to the multi kinase inhibitor. Taken together, these results suggest that a STAT5 ASO therapeutic approach may have utility for the treatment of AML and related hematologic disorders.

Hepatitis B virus X protein promotes proliferation of hepatocellular carcinoma cells by upregulating miR-181b by targeting ING5

2018 ◽  
Vol 399 (6) ◽  
pp. 611-619 ◽  
Author(s):  
Xuhua Xie ◽  
Xiaopei Xu ◽  
Changyu Sun ◽  
Zujiang Yu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cell Lines ◽  
Tumor Model ◽  
Luciferase Reporter ◽  
X Protein ◽  
B Virus

Abstract Hepatitis B virus X protein (HBx) played a key role in the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Emerging evidence has demonstrated that miR-181b and the inhibitor of growth protein 5 (ING5) participated in the pathophysiological process. However, the regulatory mechanism of HBx remained unknown. The expression of miR-181b and ING5 in HCC tissues and cell lines were examined using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Cell viability was determined using the MTT method following HCC cell lines transfection. The interaction between miR-181b and ING5 was assessed by luciferase reporter assay. The nude mice tumor model was well established to evaluate the role and biological functions of HBx on the progression of HBV-related HCC in vivo. MiR-181b was upregulated and ING5 was downregulated in HCC tissues and cell lines. As suggested by the results from in vitro and in vivo experiments, HBx downregulates the expression of the miR-181b target gene ING5, resulting in the promotion of HCC cell proliferation. HBx accelerates proliferation activity of HCC cells by increasing miR-181b expression via targeting ING5, thereby influencing the progression of HBV-related HCC.

scholarly journals Synthesis, Anti-proliferative Activity, and Molecular Docking Study of New Series of 1,3-5-Triazine Schiff Base Derivatives

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4065
Author(s):  
Hessa H. Al Rasheed ◽  
Azizah M. Malebari ◽  
Kholood A. Dahlous ◽  
Darren Fayne ◽  
Ayman El-Faham
Keyword(s):  
Schiff Base ◽  
Molecular Docking ◽  
Cell Lines ◽  
Proliferative Activity ◽  
Docking Study ◽  
Reference Compound ◽  
Molecular Docking Study ◽  
Schiff Base Derivatives ◽  
Hct 116 ◽  
Mcf 7

Based on the use of s-triazine as a scaffold, we report here a new series of s-triazine Schiff base derivatives and their anti-proliferative activity against two cancer cell lines: human breast carcinoma (MCF-7), and colon cancer (HCT-116) compared with tamoxifen as a reference compound. Several derivatives exhibited growth inhibition activity in the sub-micromolar range. The results reveal that the s-triazine Schiff base derivatives showed varied activities and that the substituents on the s-triazine core have a great effect on the anti-proliferative activity. Compounds with a piperidino and benzylamino substituent on the s-triazine moiety 4b and 4c were most effective in both cell lines compared to the reference compound used. In addition, compound 4b has a para chlorine atom on the benzylidine residue, demonstrating the most potent activity with IC50 values of 3.29 and 3.64 µM in MCF-7 and HCT-116, respectively. These results indicate that in general, the nature of the substituents on the triazine core and the type of substituent on the benzilyldene ring significantly influenced the anti-proliferative activity. The results obtained from the anti-proliferative activity and the molecular docking study indicate that s-triazine-hydrazone derivatives may be an excellent scaffold for the development of new anti-cancer agents.

scholarly journals MicroRNA-138-1-3p sensitizes sorafenib to hepatocellular carcinoma by targeting PAK5 mediated β-catenin/ABCB1 signaling pathway

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Tong-tong Li ◽  
Jie Mou ◽  
Yao-jie Pan ◽  
Fu-chun Huo ◽  
Wen-qi Du ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Kinase Inhibitor ◽  
Luciferase Reporter ◽  
Advanced Hepatocellular Carcinoma ◽  
First Line Therapy ◽  
Xenotransplantation Model

Abstract Background Sorafenib is a kinase inhibitor that is used as a first-line therapy in advanced hepatocellular carcinoma (HCC) patients. However, the existence of sorafenib resistance has limited its therapeutic effect. Through RNA sequencing, we demonstrated that miR-138-1-3p was downregulated in sorafenib resistant HCC cell lines. This study aimed to investigate the role of miR-138-1-3p in sorafenib resistance of HCC. Methods In this study, quantitative real-time PCR (qPCR) and Western Blot were utilized to detect the levels of PAK5 in sorafenib-resistant HCC cells and parental cells. The biological functions of miR-138-1-3p and PAK5 in sorafenib-resistant cells and their parental cells were explored by cell viability assays and flow cytometric analyses. The mechanisms for the involvement of PAK5 were examined via co-immunoprecipitation (co-IP), immunofluorescence, dual luciferase reporter assay and chromatin immunoprecipitation (ChIP). The effects of miR-138-1-3p and PAK5 on HCC sorafenib resistant characteristics were investigated by a xenotransplantation model. Results We detected significant down-regulation of miR-138-1-3p and up-regulation of PAK5 in sorafenib-resistance HCC cell lines. Mechanistic studies revealed that miR-138-1-3p reduced the protein expression of PAK5 by directly targeting the 3′-UTR of PAK5 mRNA. In addition, we verified that PAK5 enhanced the phosphorylation and nuclear translocation of β-catenin that increased the transcriptional activity of a multidrug resistance protein ABCB1. Conclusions PAK5 contributed to the sorafenib resistant characteristics of HCC via β-catenin/ABCB1 signaling pathway. Our findings identified the correlation between miR-138-1-3p and PAK5 and the molecular mechanisms of PAK5-mediated sorafenib resistance in HCC, which provided a potential therapeutic target in advanced HCC patients.

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