Vinorelbinin tümörle ilişkili makrofajları modüle etme ve küçük hücreli olmayan akciğer kanserinde proliferasyon ve migrasyona etkisi
Project no. 23266 · Status: Kapanmış · 2021
Summary
<p>Tumor-associated macrophages (TAMs) play key roles in tumor progression and are a critical determinant in determining the patient's response to conventional chemotherapy. Although the antiproliferative effects of classical anticancer drugs are well-known, their effects on the immune response in the tumor microenvironment and the role of these effects in cancer treatment are unknown. Here, the effect of vinorelbine, an antineoplastic agent widely used in solid cancer treatment, on M2 macrophages in lung cancer was investigated. PBMC was polarized to M2 macrophages and phenotype changes in M2 macrophages treated with vinorelbine were identified. Then, the effects of vinorelbine on expression levels of genes and proteins involved in cancer progression and on cell invasion were determined in NSCLC cells indirectly co-cultured with M2 macrophages. Vinorelbine, especially at low concentrations, reprogrammed M2 polarized macrophages to M1-like phenotype. Although M2 macrophages increased the invasion of cancer cells, vinorelbine significantly reduced this effect. M2 macrophages induced overexpression of many genes associated with tumor growth, angiogenic, invasion, and immune suppression in NSCLC cells and increased the BCL2/BAX ratio, making the cells more resistant to apoptosis. On the other hand, M2 macrophages reduced the effect of vinorelbine on lung cancer cells by downregulating p-STAT3 expression. In conclusion, the antitumor effect of vinorelbine is at least partially related to the reprogramming of the M2 macrophage to the M1 phenotype. Furthermore, the efficacy of vinorelbine therapy against TAMs at low doses may biologically explain the therapy window of metronomic vinorelbine, which may protect cancer patients from unnecessary toxic treatments. </p>