Synergistic cytotoxicity of the CDK4 inhibitor Fascaplysin in combination with EGFR inhibitor Afatinib against Non-small Cell Lung Cancer.
Afatinib
Cytotoxicity
Fascaplysin
Non-small cell lung cancer
Pleural effusion
Protein phosphorylation
Journal
Investigational new drugs
ISSN: 1573-0646
Titre abrégé: Invest New Drugs
Pays: United States
ID NLM: 8309330
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
received:
11
11
2020
accepted:
16
09
2021
pubmed:
2
10
2021
medline:
13
4
2022
entrez:
1
10
2021
Statut:
ppublish
Résumé
In the absence of suitable molecular markers, non-small cell lung cancer (NSCLC) patients have to be treated with chemotherapy with poor results at advanced stages. Therefore, the activity of the anticancer marine drug fascaplysin was tested against primary NSCLC cell lines established from pleural effusions. Cytotoxicity of the drug or combinations were determined using MTT assays and changes in intracellular phosphorylation by Western blot arrays. Fascaplysin revealed high cytotoxicity against NSCLC cells and exhibit an activity pattern different of the standard drug cisplatin. Furthermore, fascaplysin synergizes with the EGFR tyrosine kinase inhibitor (TKI) afatinib to yield a twofold increased antitumor effect. Interaction with the Chk1/2 inhibitor AZD7762 confirm the differential effects of fascplysin and cisplatin. Protein phosphorylation assays showed hypophosphorylation of Akt1/2/3 and ERK1/2 as well as hyperphosphorylation of stress response mediators of H1299 NSCLC cells. In conclusion, fascaplysin shows high cytotoxicity against pleural primary NSCLC lines that could be further boosted when combined with the EGFR TKI afatinib.
Identifiants
pubmed: 34596822
doi: 10.1007/s10637-021-01181-8
pii: 10.1007/s10637-021-01181-8
pmc: PMC8993745
doi:
Substances chimiques
Antineoplastic Agents
0
Indoles
0
Protein Kinase Inhibitors
0
fascaplysine
114719-57-2
Afatinib
41UD74L59M
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
CDK4 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinase 4
EC 2.7.11.22
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
215-223Informations de copyright
© 2021. The Author(s).
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