Interferon-α Conditioned Sensitivity to an Anti–Epidermal Growth Factor Receptor Monoclonal Antibody in a Human Lung Cancer Cell Line With Intermediate Expression of the Receptor

Abstract

Targeted therapy to the epidermal growth factor receptor (EGFR) seems to be related to its expression level on tumor cells. Interferon-alpha (IFN-alpha) induces growth inhibition but also may up-regulate the EGFR expression in some cancer cell lines. We aimed to determine whether the IFN-alpha combined with an EGFR-specific monoclonal antibody (nimotuzumab) may affect the growth of human tumor epithelial cell lines with different EGFR expression levels. H125, a lung adenosquamous carcinoma, and A431, a vulvar epidermoid carcinoma, cell lines express intermediate and high levels of EGFR, respectively, whereas MDA MB231, a breast adenocarcinoma cell line expresses undetectable levels of EGFR measured by flow cytometry/FACS. We found that IFN-alpha alone inhibited in a dose-dependent fashion the growth of all cell lines, but only up-regulated the EGFR expression in the lung carcinoma-derived cell line. Noteworthy, the combined treatment did not modify the complement-mediated cytotoxicity of the antibody although the antiproliferative activity of nimotuzumab in H125 cells in vitro increased when an IFN-alpha-conditioning treatment was used. In conclusion, this study may provide insights about the rational use of EGFR inhibitors into the immunopharmacological management of targeted therapies including the IFN-alpha for lung cancer.

Interferon-α reduces the gefitinib sensitivity of human non-small cell lung cancer

“…Previously, many studies reported that IFN-α could activate EGFR signalling by upregulating EGFR expression [ 7 , 8 ]. We investigated whether IFN-α could induce EGFR signalling activation in NSCLC cells.…”

“…There are numerous reports on preclinical studies of interferon (IFN) and its positive synergistic effect when combined with anti-EGFR agents in various tumours, such as renal cell carcinoma [ 2 ], hepatocellular carcinoma [ 3 ], and bladder carcinoma [ 4 ]. In addition, many studies have verified the positive combined effect of IFN and EGFR-TKI in human colon cancer cells [ 5 , 6 ] and head and neck cancer cells [ 7 ]; it is hypothesised that IFN can activate EGFR signalling by upregulating EGFR [ 8 ]. As EGFR-TKI has been applied primarily in advanced NSCLC, our experiment was designed to explore the combinational or sequential role of IFN-α and gefitinib in NSCLC cells possessing different genotypes, and to determine whether the synergistic effect of this combination therapy can occur in NSCLC.…”

Sensitisation of human lung adenocarcinoma A549 cells to radiotherapy by Nimotuzumab is associated with enhanced apoptosis and cell cycle arrest in the G2/M phase

“…In contrast, H460, H1299 and H1975 cells show a low level of surface EGFR expression (Akashi et al, 2008). H125, a lung adenosquamous carcinoma cell line expresses intermediate level of EGFR (Diaz et al, 2009). Even in similar lung adenocarcinoma cell lines with increased expression of EGFR, some overexpress wild-type EGFR, while others overexpress mutant-type EGFR.…”

Interferon-α Promotes the Expression of Cancer Stem Cell Markers in Oral Squamous Cell Carcinoma

“…IFNα pre-treatment followed by a combination of IFNα plus Erlotinib significantly enhanced the sensitivity of colon cancer cell lines 31 . IFNα enhanced the sensitivity to an anti-epidermal growth factor receptor monoclonal antibody (Nimotuzumab) in a human lung cancer cell line with intermediate expression of the receptor 32 . Low dose of IFNα intensified antineoplastic effect of a histone deacetylase -inhibitor, valproic acid, and the mammalian target of rapamycin inhibitor everolimus in prostate cancer cells 33 .…”