4Ei-10 interdiction of oncogenic cap-mediated translation as therapy for non-small cell lung cancer.
Blake A JacobsonZeeshan AhmadSierra ChenGabriella WalduskyMaxwell DillenburgEmilia StoianDaniel A CambronAnil J PatelManish R PatelCarston R WagnerRobert A KratzkePublished in: Investigational new drugs (2020)
In order to suppress 5' cap-mediated translation a highly available inhibitor of the interaction between the 5' mRNA cap and the eIF4E complex has been developed. 4Ei-10 is a member of the class of ProTide compounds and has elevated membrane permeability and is a strong active chemical antagonist for eIF4E. Once taken up by cells it is converted by anchimeric activation of the lipophilic 2-(methylthio) ethyl protecting group and after that Hint1 P-N bond cleavage to N7-(p-chlorophenoxyethyl) guanosine 5'-monophosphate (7-Cl-Ph-Ethyl-GMP). Using this powerful interaction, it has been demonstrated that 4Ei-10 inhibits non-small cell lung cancer (NSCLC) cell growth. In addition, treatment of NSCLC cells with 4Ei-10 results in suppression of translation and diminished expression of a cohort of cellular proteins important to maintaining the malignant phenotype and resisting apoptosis such as Bcl-2, survivin, and ornithine decarboxylase (ODC). Finally, as a result of targeting the translation of anti-apoptotic proteins, NSCLC cells are synergized to be more sensitive to the existing anti-neoplastic treatment gemcitabine currently used in NSCLC therapy.
Keyphrases
- cell cycle arrest
- induced apoptosis
- small cell lung cancer
- cell death
- endoplasmic reticulum stress
- advanced non small cell lung cancer
- oxidative stress
- stem cells
- squamous cell carcinoma
- staphylococcus aureus
- radiation therapy
- escherichia coli
- cell proliferation
- transcription factor
- mesenchymal stem cells
- pseudomonas aeruginosa
- candida albicans
- combination therapy
- biofilm formation
- dna binding
- rectal cancer