frondoside-a and Neoplasm-Metastasis

A major challenge for oncologists and pharmacologists is to develop less toxic drugs that will improve the survival of lung cancer patients. Frondoside A is a triterpenoid glycoside isolated from the sea cucumber, Cucumaria frondosa and was shown to be a highly safe compound. We investigated the impact of Frondoside A on survival, migration and invasion in vitro, and on tumor growth, metastasis and angiogenesis in vivo alone and in combination with cisplatin. Frondoside A caused concentration-dependent reduction in viability of LNM35, A549, NCI-H460-Luc2, MDA-MB-435, MCF-7, and HepG2 over 24 hours through a caspase 3/7-dependent cell death pathway. The IC50 concentrations (producing half-maximal inhibition) at 24 h were between 1.7 and 2.5 µM of Frondoside A. In addition, Frondoside A induced a time- and concentration-dependent inhibition of cell migration, invasion and angiogenesis in vitro. Frondoside A (0.01 and 1 mg/kg/day i.p. for 25 days) significantly decreased the growth, the angiogenesis and lymph node metastasis of LNM35 tumor xenografts in athymic mice, without obvious toxic side-effects. Frondoside A (0.1-0.5 µM) also significantly prevented basal and bFGF induced angiogenesis in the CAM angiogenesis assay. Moreover, Frondoside A enhanced the inhibition of lung tumor growth induced by the chemotherapeutic agent cisplatin. These findings identify Frondoside A as a promising novel therapeutic agent for lung cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Caspases; Cell Line, Tumor; Cell Movement; Cell Survival; Enzyme Activation; Female; Glycosides; Humans; Lung; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Neovascularization, Pathologic; Triterpenes

Metastasis and invasion are among the main causes of death in patients with malignant tumors. The aim of this study was to determine the anti-invasive activity of frondoside A against human breast cancer cells. We investigated the inhibitory effect of frondoside A on cell clonogenicity, invasion and migration in TPA-stimulated human breast cancer cells at non-cytotoxic concentrations. Frondoside A significantly attenuated TPA-induced colony formation, invasion and migration in MBA-MB-231 human breast cancer cells. Induction of MMP-9 is especially important for the metastasis of many cancer tumor cell types. Additionally, we found that frondoside A suppresses TPA-induced MMP-9 enzymatic activity, secretion and expression. This effect was associated with reduced activation of AP-1 and NF-κB, and correlated with enhanced expression of TIMP-1 and TIMP-2. Frondoside A significantly inhibited the TPA-induced MMP-9 expression possibly via the suppression of AP-1 and NF-κB signaling pathways. Frondoside A reduces the activation of the PI3K/Akt, ERK1/2 and p38 MAPK signals. These results suggest that the anti-metastatic effects of frondoside A on human breast cancer cells might result from inhibited TPA activation of AP-1 and NF-κB and reduced TPA activation of PI3K/Akt, ERK1/2 and p38 MAPK signals, ultimately leading to downregulation of MMP-9 expression. These results indicate the role of frondoside A in metastasis and its underlying molecular mechanisms, thus, suggesting frondoside A as a chemopreventive agent for metastatic breast cancer.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Female; Glycosides; Humans; MAP Kinase Signaling System; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Neoplasm Metastasis; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; RNA Interference; RNA, Small Interfering; Tetradecanoylphorbol Acetate; Transcription Factor AP-1; Triterpenes