bergamottin and Lung-Neoplasms

Bergamottin (BGM) is a naturally occurring furanocoumarin and is known to inhibit the growth of tumor cells. However, there is no available evidence that BGM has an inhibitory effect on cancer metastasis, specifically on the epithelial-to-mesenchymal transition (EMT) process in the malignant cells. Here we aimed to evaluate the antimetastatic potential of BGM in human lung adenocarcinoma cells. Our results demonstrate that BGM can block EMT, and observed inhibition was accompanied by downregulation of fibronectin, vimentin, N-cadherin, twist and snail expression, and upregulation of occludin and E-cadherin. Interestingly, transforming growth factor-β (TGF-β)-induced upregulation of fibronectin, vimentin, N-cadherin, twist and snail, and downregulation of occludin and E-cadherin, were abrogated by BGM treatment. Moreover, the treatment of BGM repressed TGF-β-induced cell invasive potential. BGM treatment also inhibited multiple oncogenic cascades such as PI3K/Akt/mTOR. Overall, the results demonstrate the potential antimetastatic activity of BGM against lung cancer cells.

Topics: A549 Cells; Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; Carcinogenesis; Cell Line, Tumor; Down-Regulation; Epithelial-Mesenchymal Transition; Furocoumarins; Humans; Lung; Lung Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; Oncogenes; Signal Transduction; Up-Regulation

The objective of the present study was to investigate the in vitro and in vivo anticancer properties of bergamottin, a natural furanocoumarin, against human non-small cell lung carcinoma (NSCLC) A549 cells. We also studied its effect on cell proliferation, cell cycle arrest, cell invasion, cell migration as well as cell apoptosis. Antiproliferative activity of bergamottin was estimated by the MTT assay. Phase contrast and fluorescence microscopy as well as flow cytometry using Annexin V-FITC assay were used to study induction of apoptosis by bergamottin in these cells. The effects of bergamottin on cell cycle phase distribution as well as on mitochondrial membrane potential were also demonstrated using flow cytometry. In vitro wound healing assay was used to study the effect of bergamottin on cell migration. The effects of bergamottin on tumor progression were also observed using a nude mouse model. The mice were divided into 4 groups and treated with bergamottin injected intraperitoneally. Bergamottin induced dose-dependent as well as time-dependent cytotoxic effects as well as inhibition of colony formation in the A549 cancer cells. Bergamottin also suppressed cancer cell invasion as well as cancer cell migration. Phase contrast microscopy and fluorescence microscopy revealed that bergamottin induced cell shrinkage, chromatin condensation and the cells became rounded and detached from each other. Bergamottin also induced a potent cell cycle arrest at the G2/M phase of the cell cycle. Experiments in mice showed that 25, 50 and 100 mg/kg bergamottin injection reduced the tumor weight from 1.61 g in the phosphate-buffered saline (PBS)-treated group (control) to 1.21, 0.42 and 0.15 g in the bergamottin-treated groups, respectively. The results of the present study revealed that bergamottin was able to inhibit lung cancer cell growth both in a cell model and a xenograft mouse model by inducing apoptosis, mitochondrial membrane potential loss, G2/M cell cycle arrest as well as inhibiting cell migration and invasion.

Topics: A549 Cells; Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Citrus; Female; Furocoumarins; G2 Phase Cell Cycle Checkpoints; Humans; Lung Neoplasms; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness