scholarly journals The Protective Role of Decorin in Hepatic Metastasis of Colorectal Carcinoma

Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1199
Author(s):  
Andrea Reszegi ◽  
Zsolt Horváth ◽  
Katalin Karászi ◽  
Eszter Regős ◽  
Victoria Postniková ◽  
...  
Keyword(s):  
Colon Carcinoma ◽  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Metastatic Tumor ◽  
Human Colon ◽  
Tissue Microarrays ◽  
Tumor Formation ◽  
Antitumor Action

Decorin, the prototype member of the small leucine-rich proteoglycan gene family of extracellular matrix (ECM) proteins, acts as a powerful tumor suppressor by inducing the p21Waf1/Cip1 cyclin-dependent kinase inhibitor, as well as through its ability to directly bind and block the action of several tyrosine kinase receptors. Our previous studies suggested that the lack of decorin promotes hepatic carcinogenesis in mice. Based on this, we set out to investigate whether excess decorin may protect against the liver metastases of colon carcinoma. We also analyzed the effect of decorin in tissue microarrays of human colon carcinoma liver metastasis and examined whether the tumor cells can directly influence the decorin production of myofibroblasts. In humans, low levels of decorin in the liver facilitated the development of colon carcinoma metastases in proportion with more aggressive phenotypes, indicating a possible antitumor action of the proteoglycan. In vitro, colon carcinoma cells inhibited decorin expression in LX2 hepatic stellate cells. Moreover, liver-targeted decorin delivery in mice effectively attenuated metastasis formation of colon cancer. Overexpressed decorin reduced the activity of multiple receptor tyrosine kinases (RTKs) including the epidermal growth factor receptor (EGFR), an important player in colorectal cancer (CRC) pathogenesis. Downstream of that, we observed weakened signaling of ERK1/2, PLCγ, Akt/mTOR, STAT and c-Jun pathways, while p38 MAPK/MSK/CREB and AMPK were upregulated culminating in enhanced p53 function. In conclusion, decorin may effectively inhibit metastatic tumor formation in the liver.

scholarly journals A New Series of Indeno[1,2-c]pyrazoles as EGFR TK Inhibitors for NSCLC Therapy

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 485
Author(s):  
Ahmet Özdemir ◽  
Halilibrahim Ciftci ◽  
Belgin Sever ◽  
Hiroshi Tateishi ◽  
Masami Otsuka ◽  
...  
Keyword(s):  
In Silico ◽  
Mononuclear Cells ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Antitumor Agent ◽  
In Vitro Assays ◽  
Antitumor Action ◽  
Peripheral Blood Mononuclear ◽  
Ic50 Value

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death throughout the world. Due to the shortcomings of traditional chemotherapy, targeted therapies have come into prominence for the management of NSCLC. In particular, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy has emerged as a first-line therapy for NSCLC patients with EGFR-activating mutations. In this context, new indenopyrazoles, which were prepared by an efficient microwave-assisted method, were subjected to in silico and in vitro assays to evaluate their potency as EGFR TK-targeted anti-NSCLC agents. Compound 4 was the most promising antitumor agent towards A549 human lung adenocarcinoma cells, with an IC50 value of 6.13 µM compared to erlotinib (IC50 = 19.67 µM). Based on its low cytotoxicity to peripheral blood mononuclear cells (PBMCs), it can be concluded that compound 4 exerts selective antitumor action. This compound also inhibited EGFR TK with an IC50 value of 17.58 µM compared to erlotinib (IC50 = 0.04 µM) and induced apoptosis (56.30%). Taking into account in silico and in vitro data, compound 4 stands out as a potential EGFR TKI for the treatment of NSCLC.

The influence of extracts from Rubus caesius leaves on human colon carcinoma cells cultured in vitro

Planta Medica ◽  
2014 ◽  
Vol 80 (16) ◽  
Author(s):  
R Paduch ◽  
M Tomczyk ◽  
A Wiater ◽  
A Dudek ◽  
M Pleszczynska ◽  
...  
Keyword(s):  
Colon Carcinoma ◽  
Human Colon ◽  
Carcinoma Cells ◽  
Colon Carcinoma Cells ◽  
Human Colon Carcinoma ◽  
Cells Cultured

scholarly journals Synthesis of Some Polysubstituted Nicotinonitriles and Derived Pyrido[2,3-d]pyrimidines asIn VitroCytotoxic and Antimicrobial Candidates

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Hassan M. Faidallah ◽  
Sherif A. F. Rostom ◽  
Khalid A. Khan
Keyword(s):  
Cell Line ◽  
Colon Carcinoma ◽  
Human Tumor ◽  
Human Colon ◽  
Pyrimidine Ring ◽  
Inhibitory Effect ◽  
Breast Adenocarcinoma ◽  
Human Tumor Cell Lines ◽  
E Coli

The synthesis of polysubstituted pyridines, in addition to some derived pyrido[2,3-d]pyrimidine ring systems supported with chemotherapeutically active functionalities, is described. They were evaluated for theirin vitrocytotoxic effects against three different human tumor cell lines (human colon carcinoma HT29, hepatocellular carcinoma Hep-G2, and Caucasian breast adenocarcinoma MCF7). Nine compounds displayed variable cytotoxic potential, among which alkylthio analogs33,34, and37emerged as the most active members, being almost twice as active as doxorubicin against the colon carcinoma HT29 cell line. In addition, the same three analogs showed a clear differential cytotoxic profile as they exhibited a marginal inhibitory effect on the growth of the normal nontransformed human foreskin fibroblast Hs27 cell line. Meanwhile, nineteen compounds were able to exhibit significant antibacterial activity against both Gram-positive and Gram-negative bacteria, together with moderate antifungal activities. The pyrido[2,3-d]pyrimidine-2(1H)-thione30together with its alkylthio derivatives33and34stemmed as the most active antimicrobial members being equipotent to ampicillin againstS. aureus,E. coli,andP. aeruginosa,together with a noticeable antifungal activity againstC. albicans.Compounds33and34could be considered as a promising template for possible dual antimicrobial-anticancer candidates.

scholarly journals Enhanced Anticancer Activity of Nanoformulation of Dasatinib against Triple-Negative Breast Cancer by Reduced Metabolic Degradation

2021 ◽  
Author(s):  
Fatemah Bahman ◽  
Valeria Pittalà ◽  
Mohamed Haider ◽  
Khaled Greish
Keyword(s):  
Breast Cancer ◽  
Anticancer Activity ◽  
Triple Negative Breast Cancer ◽  
Tyrosine Kinases ◽  
Triple Negative ◽  
Growth Factor Receptor ◽  
Initial Response ◽  
Response To Chemotherapy

Triple negative breast cancer (TNBC) is the most aggressive breast cancer accounting for around 15% of identified breast cancer cases. TNBC, by lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), is unresponsive to current targeted therapies. Existing treatment relies on chemotherapeutic treatment but, despite an initial response to chemotherapy, the inception of resistance and relapse is unfortunately common. Dasatinib is an approved second-generation inhibitor of multiple tyrosine kinases and literature data strongly support its use in the management of TNBC. However, dasatinib binds to plasma proteins and undergoes extensive metabolism through oxidation and conjugation. To protect dasatinib from fast pharmacokinetic degradation and to prolong its activity, it was encapsulated on poly(styrene-co-maleic acid) (SMA) micelles. The obtained SMA-dasatinib nanoparticles (NPs) were evaluated for their physicochemical properties, in vitro antiproliferative activity in different TNBC cell lines, and in vivo anticancer activity in a syngeneic model of breast cancer. Obtained results showed that SMA-dasatinib is more potent against 4T1 TNBC tumor growth in vivo compared to free drug. This enhanced effect was ascribed to the encapsulation of the drug protecting it from a rapid metabolism. Our finding highlights the often-overlooked value of nanoformulations in protecting its cargo from degradation. Overall, results may provide an alternative therapeutic strategy for TNBC management.

scholarly journals Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells

2018 ◽  
Vol 11 (549) ◽  
pp. eaat7951 ◽  
Author(s):  
Daniel M. Foulkes ◽  
Dominic P. Byrne ◽  
Wayland Yeung ◽  
Safal Shrestha ◽  
Fiona P. Bailey ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Small Molecule ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Drug Repurposing ◽  
Protein Kinase Inhibitors ◽  
Cellular Mechanisms ◽  
Cellular Analysis

A major challenge associated with biochemical and cellular analysis of pseudokinases is a lack of target-validated small-molecule compounds with which to probe function. Tribbles 2 (TRIB2) is a cancer-associated pseudokinase with a diverse interactome, including the canonical AKT signaling module. There is substantial evidence that human TRIB2 promotes survival and drug resistance in solid tumors and blood cancers and therefore is of interest as a therapeutic target. The unusual TRIB2 pseudokinase domain contains a unique cysteine-rich C-helix and interacts with a conserved peptide motif in its own carboxyl-terminal tail, which also supports its interaction with E3 ubiquitin ligases. We found that TRIB2 is a target of previously described small-molecule protein kinase inhibitors, which were originally designed to inhibit the canonical kinase domains of epidermal growth factor receptor tyrosine kinase family members. Using a thermal shift assay, we discovered TRIB2-binding compounds within the Published Kinase Inhibitor Set (PKIS) and used a drug repurposing approach to classify compounds that either stabilized or destabilized TRIB2 in vitro. TRIB2 destabilizing agents, including the covalent drug afatinib, led to rapid TRIB2 degradation in human AML cancer cells, eliciting tractable effects on signaling and survival. Our data reveal new drug leads for the development of TRIB2-degrading compounds, which will also be invaluable for unraveling the cellular mechanisms of TRIB2-based signaling. Our study highlights that small molecule–induced protein down-regulation through drug “off-targets” might be relevant for other inhibitors that serendipitously target pseudokinases.

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