A small library of chalcones induce liver cancer cell death through Akt phosphorylation inhibition

Autor: Daniele Passarella, Çiğdem Tepe Karaca, Irem Durmaz Sahin, Michael S. Christodoulou, Rengul Cetin-Atalay, Ece Akhan Güzelcan, Altay Koyas
Přispěvatelé: Şahin, İrem Durmaz (ORCID 0000-0001-5037-7883 & YÖK ID 303825), Christodoulou, Michael S., Güzelcan, Ece Akhan, Koyaş, Altay, Karaca, Çiğdem, Passarella, Daniele, Çetin-Atalay, Rengül, School of Medicine
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Hepatocellular carcinoma
NF-Kappa-B
Pathway
Paclitaxel
Scaffold
Therapy
Kinases
Growth
PTEN
lcsh:Medicine
Drug development
Antineoplastic Agents
Apoptosis
Models
Biological
behavioral disciplines and activities
01 natural sciences
Article
03 medical and health sciences
Chalcones
0302 clinical medicine
Cell Line
Tumor
medicine
Humans
Phosphorylation
lcsh:Science
Protein kinase B
Science and technology
PI3K/AKT/mTOR pathway
Cell Proliferation
Multidisciplinary
Cell Death
Dose-Response Relationship
Drug
Molecular Structure
biology
010405 organic chemistry
Chemistry
Cell growth
Small molecules
Cell Cycle
lcsh:R
Cancer
Cell cycle
medicine.disease
0104 chemical sciences
Cell culture
030220 oncology & carcinogenesis
Cancer research
biology.protein
lcsh:Q
Liver cancer
Proto-Oncogene Proteins c-akt
psychological phenomena and processes
Zdroj: Scientific Reports, Vol 10, Iss 1, Pp 1-9 (2020)
Scientific Reports
ISSN: 2045-2322
DOI: 10.1038/s41598-020-68775-9
Popis: Hepatocellular carcinoma (HCC) ranks as the fifth most common and the second deadliest cancer worldwide. HCC is extremely resistant to the conventional chemotherapeutics. Hence, it is vital to develop new treatment options. Chalcones were previously shown to have anticancer activities in other cancer types. In this study, 11 chalcones along with quercetin, papaverin, catechin, Sorafenib and 5FU were analyzed for their bioactivities on 6 HCC cell lines and on dental pulp stem cells (DPSC) which differentiates into hepatocytes, and is used as a model for untransformed control cells. 3 of the chalcones (1, 9 and 11) were selected for further investigation due to their high cytotoxicity against liver cancer cells and compared to the other clinically established compounds. Chalcones did not show significant bioactivity (IC 50> 20 μ M) on dental pulp stem cells. Cell cycle analysis revealed that these 3 chalcone-molecules induced SubG1/G1 arrest. Akt protein phosphorylation was inhibited by these molecules in PTEN deficient, drug resistant, mesenchymal like Mahlavu cells leading to the activation of p21 and the inhibition of NFκB-p65 transcription factor. Hence the chalcones induced apoptotic cell death pathway through NFκB-p65 inhibition. On the other hand, these molecules triggered p21 dependent activation of Rb protein and thereby inhibition of cell cycle and cell growth in liver cancer cells. Involvement of PI3K/Akt pathway hyperactivation was previously described in survival of liver cancer cells as carcinogenic event. Therefore, our results indicated that these chalcones can be considered as candidates for liver cancer therapeutics particularly when PI3K/Akt pathway involved in tumor development.
Scientific and Technological Research Council of Turkey (TÜBİTAK); COST Action; European Union (European Union); Horizon 2020
Databáze: OpenAIRE
Externí odkaz: