3-(4-dimethylamino-naphthalen-1-ylmethylene)-1-3-dihydro-indol-2-one and Lung-Neoplasms

In lung adenocarcinoma, loss of p53 and PTEN in tumors are associated with decreased response to chemotherapy and decreased survival. A means to pharmacologically upregulate p53 and PTEN protein expression could improve the prognosis of patients with p53- and PTEN-deficient tumors. In the present study we revealed that vascular endothelial growth factor receptor 3 (VEGFR3) inhibition in lung adenocarcinoma cells was associated with improved expression levels of both p53 and PTEN in the tumor-associated macrophage (TAM) microenvironment. Inhibition of VEGFR3 in lung adenocarcinoma cells was associated with growth arrest and decreased migration and invasion. The upregulation of p53 and PTEN protein expression after VEGFR3 inhibition decreased chemotherapy resistance and improved chemosensitivity in co-cultured A549 cells in which p53 and PTEN expression were decreased. Finally, we demonstrated that TAMs promoted the expression of VEGF-C and its receptor VEGFR3. Western blot analysis revealed the co-cultured A549 cells with TAMs are a primary source of VEGF-C and VEGFR3 in the tumor microenvironment. Our studies revealed that VEGFR3 inhibition may be a pharmacological means to upregulate p53 and PTEN protein expression and improve the outcome of patients with p53- and PTEN-deficient tumors.

Topics: A549 Cells; Adenocarcinoma; Adenocarcinoma of Lung; Cell Movement; Cell Proliferation; Doxorubicin; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Indoles; Lung Neoplasms; Macrophages; Naphthalenes; PTEN Phosphohydrolase; THP-1 Cells; Tumor Microenvironment; Tumor Suppressor Protein p53; Up-Regulation; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-3

The metastatic spread of tumor cells via lymphatic vessels affects the relapse of tumor patients. New lymphatic vessel formation, including lymphangiogenesis, is promoted in the tumor environment. The lymphangiogenic factor VEGF-C can mediate lymphatic vessel formation and induce tumor metastasis by binding with FLT4. In melanoma, metastasis via lymphatics such as lymph nodes is one of the main predictors of poor outcome. Thus, we investigated whether blockade of FLT4 can reduce metastasis via the suppression of lymphatic capillaries. Proliferative lymphatic capillaries in melanoma were estimated by immunohistochemistry using FLT4 antibody after the injection of the FLT4 antagonist MAZ51. The numbers of tumor modules in metastasised lungs were calculated by gross examination and lymphatic related factors were examined by qRT-PCR. MAZ51 injection resulted in the suppression of tumor size and module number and the inhibition of proliferative lymphatic vessels in the intratumoral region in the lung and proliferating melanoma cells in the lung compared to those of untreated groups. Additionally, high FLT4 and TNF-alpha were detected in melanoma-induced tissue, while lymphatic markers such as VEGF-C, FLT4 and Prox-1 were significantly decreased in MAZ51 treated groups, implying that anti-lymphangiogenesis by MAZ51 may provide a potential strategy to prevent tumor metastasis in melanoma and high number of lymphatic capillaries could be used diagnosis for severe metastasis.

Topics: Animals; Antibodies, Monoclonal; Biomarkers, Tumor; Gene Expression; Homeodomain Proteins; Indoles; Injections, Intravenous; Lung Neoplasms; Lymph Nodes; Lymphangiogenesis; Lymphatic Metastasis; Lymphatic Vessels; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Naphthalenes; Tumor Burden; Tumor Microenvironment; Tumor Necrosis Factor-alpha; Tumor Suppressor Proteins; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-3