Ferumoxytol and CpG oligodeoxynucleotide 2395 synergistically enhance antitumor activity of macrophages against NSCLC with EGF[R.sup.L858R/T790M] mutation

• Published in: International journal of nanomedicine p. 4503
• Main Authors: Wang, Guoqun, Zhao, Jiaojiao, Zhang, Meiling, Wang, Qian, Chen, Bo, Hou, Yayi, Lu, Kaihua
• Format: Journal Article
• Language: English
• Published: Dove Medical Press Limited 01.06.2019
• Subjects: Analysis; Cancer; Cancer treatment; Cell cycle; Drug resistance; Epidermal growth factors; Ferumoxytol; Gene expression; Genes; Genetic aspects; Health aspects; Immune response; Interleukins; Lung cancer; Macrophages; Messenger RNA; Necrosis; Nitric oxide; Nitrogen oxides; Non-small cell lung cancer; Phenols (Class of compounds); Polymerase chain reaction; Proteins; Respiratory system agents; RNA; Scientific equipment industry; Small cell lung cancer; Tumors; Tyrosine; United States; China
• ISSN: 1178-2013; 1178-2013
• DOI: 10.2147/IJN.S193583

Purpose: Drug resistance is a major challenge for epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) treatment of lung cancer. Ferumoxytol (FMT) drives macrophage (M[PHI]) transformation towards a Ml-like phenotype and thereby inhibits tumor growth. CpG oligodeoxynucleotide 2395 (CpG), a toll-like receptor 9 (TLR9) agonist, is an effective therapeutic agent to induce anticancer immune responses. Herein, the effect of co-administered FMT and CpG on M[PHI] activation for treating non-small cell lung cancer (NSCLC) was explored. Methods: The mRNA expression levels of Ml-like genes in RAW 264.7 M[PHI] cells stimulated by FMT, CpG and FMT and CpG (FMT/CpG) were evaluated by quantitative reverse transcription PCR (qRT-PCR). Then, the effects of FMT/CpG-pretreated M[PHI] supernatant on apoptosis and proliferation of H1975 cells were detected by flow cytometry, and the expression of EGFR and its downstream signaling pathway in H1975 cells were explored by western blotting. Finally, a HI975 cell xenograft mouse model was used to study the antitumor effect of the combination of FMT and CpG in vivo. Results: FMT and CpG synergistically enhanced Ml-like gene expression in M[PHI], including tumor necrosis factor-[alpha], interleukin (IL)-12, IL-l[alpha], IL-l[beta], IL-6 and inducible nitric oxide synthase (iNOS). FMT/CpG-pretreated M[PHI] supernatant inhibited proliferation and induced apoptosis of H1975 cells, accompanied by down-regulation of cell cycle-associated proteins and up-regulation of apoptosis-related proteins. Further studies indicated that the FMT/CpG-pretreated M[PHI] supernatant suppressed p-EGFR and its downstream AKT/mammalian target of rapamycin signaling pathway in H1975 cells. Furthermore, FMT/CpG suppressed tumor growth in mice accompanied by a decline in the EGFR-positive tumor cell fraction and increased Ml phenotype macrophage infiltration. Conclusion: FMT acted synergistically with CpG to activate M[PHI] for suppressed proliferation and promoted apoptosis of NSCLC cells via EGFR signaling. Thus, combining FMT and CpG is an effective strategy for the treatment of NSCLC with EGF[R.sup.L858R/T790M] mutation. Keywords: ferumoxytol, CpG oligodeoxynucleotide, macrophages, non-small cell lung cancer, epidermal growth factor receptor