Cisplatin treatment induced interleukin 6 and 8 production alters lung adenocarcinoma cell migration in an oncogenic mutation dependent manner

Abstract

Background: The predominant metastatic site of lung cancer (LC) is the brain. Although outdated, conventional cisplatin treatment is still the main therapeutic approach for patients with advanced non-small cell lung cancer (NSCLC), since targeted therapy that offers better tumor control is not always possible. In the present study brain metastasis associated cytokine expression was investigated in primary NSCLC adenocarcinoma (AC) tissues with known oncogenic mutations in the presence or absence of platina based and tyrosine kinase inhibitor (TKI) drugs. Methods: Primary lung tumor samples were isolated, DNA was sequenced and then the samples were grouped based on mutation. Experiments were also performed using KRAS mutant A549 and EGFR mutant PC-9 cells. Drug response was analyzed in three dimensional (3D) tissue cultures. We assessed drug response and IL-6 and IL-8 cytokine expression in relation to cellular invasion using ATP dependent cell viability, qRT-PCR analysis, cytokine bead array, and migration assay. Results: In 3D co-cultures, primary NSCLC derived cells harboring EGFR mutation responded better to erlotinib treatment than KRAS mutant or KRAS/EGFR wild type (WT) cancer cells. In contrast, under the same culture conditions KRAS/EGFR WT or KRAS mutant cancer cells are more sensitive to cisplatin than EGFR mutant cells. Drug response and pro-inflammatory cytokine production varied depending on the driver mutations. Cisplatin but not erlotinib increased both IL-6 and IL-8 secretion and only IL-6 increased cellular migration and proliferation. Conclusion: In vitro assays are available to determine the response to planned therapeutic approach of lung cancer subtypes. The sequence of administration of therapeutic drugs determines cytokine production and therefore therapeutic response.

Pan-drug and drug-specific mechanisms of 5-FU, irinotecan (CPT-11), oxaliplatin, and cisplatin identified by comparison of transcriptomic and cytokine responses of colorectal cancer cells

“…Optimizing this induction both in terms of identity and magnitude is critical for maximizing the anti-tumor immune effects of chemotherapy and avoiding cytokine storm [ 58 ]. Some work has been done to evaluate the effects of 5-FU, CPT-11, oxaliplatin, and cisplatin on cytokine levels [ 57 , 59 , 60 ], but none have compared directly across all four drugs, clinically relevant combinations, and p53 status.…”

Toll‐like receptor 4 is activated by platinum and contributes to cisplatin‐induced ototoxicity

“…IL‐8 secretion was previously reported as marker of TLR4 activation in HEK‐hTLR4 cells and was chosen for our experiments using related cell lines (Schmidt et al, 2010). In addition, both IL‐6 and IL‐8 have been reported to be upregulated by cisplatin in human cells (Kiss et al, 2020), while mice do not contain a true gene ortholog for IL8 precluding its direct characterization. Colorimetric protein assays were conducted using commercial human IL‐8 ELISA and mouse IL‐6 ELISA kits (Invitrogen; 88‐8086, 88‐7064) according to the manufacturer’s protocol.…”

The Influence of Different Anti-PD-1 Monoclonal Antibody Concentrations On T Cell Activation in in - Vitro Culture – A Preliminary Study

“…We also observed a signi cantly higher percentage of cells expressing receptors for interleukin-2 (CD25) and interleukin-4 (CD124) in CD4positive cells after nivolumab treatment compared with the control. IL-2 is critical for T cells to polarize into cytotoxic T cells and activate natural killer cells 20 . Similarly, IL-4 is involved in activating NK cells, which play a leading role in tumor apoptosis activation 21 .…”