vinorelbine and Liver-Neoplasms

Cancer invasion and metastasis are the leading causes of death. The process of metastasis or tumor cell dissemination is still much of a mystery. Emerging evidence has shown that epithelial-mesenchymal transition (EMT) plays a vital role in the progression of malignant tumor including the inducing cell invasion and metastasis as well as promoting drug resistance. Vinorelbine is a traditional chemotherapeutic agent for treatment of lung cancer and breast cancer by the selectivity to mitotic microtubules. The aim of this study was to investigate the effect of vinorelbine on three metastatic cancer cells including lung cancer (H1975), liver cancer (HepG2), and colon cancer (HCT116) cells through inhibition of metastatic abilities and EMT program. Vinorelbine inhibited the cancer cell proliferation by MTT and colony formation assays and inducing G2/M arrest and cell apoptosis via regulation of Bax, Bcl-2, and Bcl-xL. Vinorelbine decrease the migration and invasion ability of the cancer cells by wound healing assay and Tran swell test. The molecular mechanisms of vinorelbine suppressing the metastatic phenotypes of cancer cells through modulation of E-cadherin, N-cadherin, vimentin and transcription factors Snail, MMP-2 and MMP-9. Our results demonstrated that vinorelbine inhibited the cancer cell metastasis through a reduction in metastatic mobility, such as migration, invasion, and the EMT. It provided the evidence that vinorelbine can be used alone or with other agents for treatment of metastatic lung cancer, liver cancer and colon cancer.

Topics: Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colonic Neoplasms; Epithelial-Mesenchymal Transition; G2 Phase Cell Cycle Checkpoints; Humans; Liver Neoplasms; Lung Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Tubulin Modulators; Vinorelbine

New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC₅₀ = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes.

Topics: Animals; Antineoplastic Agents; Caco-2 Cells; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cytochrome P-450 Enzyme Inhibitors; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Imidazoles; Indoles; Liver Neoplasms; Membrane Potential, Mitochondrial; Mice; Microsomes, Liver; Mitosis; Permeability; Polymerization; Pyridines; Reactive Oxygen Species; Rhabdomyosarcoma; Solubility; Structure-Activity Relationship; Tubulin; Tubulin Modulators